Long QT interval in Turner syndrome--a high prevalence of LQTS gene mutations.

PubMed

Trolle, Christian; Mortensen, Kristian H; Pedersen, Lisbeth N; Berglund, Agnethe; Jensen, Henrik K; Andersen, Niels H; Gravholt, Claus H

2013-01-01

QT-interval prolongation of unknown aetiology is common in Turner syndrome. This study set out to explore the presence of known long QT mutations in Turner syndrome and to examine the corrected QT-interval (QTc) over time and relate the findings to the Turner syndrome phenotype. Adult women with Turner syndrome (n = 88) were examined thrice and 68 age-matched healthy controls were examined once. QTc was measured by one blinded reader (intra-reader variability: 0.7%), and adjusted for influence of heart rate by Bazett's (bQTc) and Hodges's formula (hQTc). The prevalence of mutations in genes related to Long QT syndrome was determined in women with Turner syndrome and a QTc >432.0 milliseconds (ms). Echocardiographic assessment of aortic valve morphology, 24-hour blood pressures and blood samples were done. The mean hQTc in women with Turner syndrome (414.0 ± 25.5 ms) compared to controls (390.4 ± 17.8 ms) was prolonged (p<0.001) and did not change over time (416.9 ± 22.6 vs. 415.6 ± 25.5 ms; p =0.4). 45,X karyotype was associated with increased hQTc prolongation compared to other Turner syndrome karyotypes (418.2 ± 24.8 vs. 407.6 ± 25.5 ms; p = 0.055). In women with Turner syndrome and a bQTc >432 ms, 7 had mutations in major Long QT syndrome genes (SCN5A and KCNH2) and one in a minor Long QT syndrome gene (KCNE2). There is a high prevalence of mutations in the major LQTS genes in women with TS and prolonged QTc. It remains to be settled, whether these findings are related to the unexplained excess mortality in Turner women. NCT00624949. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol/sid/S0001FLI/selectaction/View/ts/3/uid/U000099E.

Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer.

PubMed

Durairaj, Chandrasekar; Ruiz-Garcia, Ana; Gauthier, Eric R; Huang, Xin; Lu, Dongrui R; Hoffman, Justin T; Finn, Richard S; Joy, Anil A; Ettl, Johannes; Rugo, Hope S; Zheng, Jenny; Wilner, Keith D; Wang, Diane D

2018-03-01

The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.

Xenon does not increase heart rate-corrected cardiac QT interval in volunteers and in patients free of cardiovascular disease.

PubMed

Neukirchen, Martin; Schaefer, Maximilian S; Kern, Carolin; Brett, Sarah; Werdehausen, Robert; Rellecke, Philipp; Reyle-Hahn, Matthias; Kienbaum, Peter

2015-09-01

Impaired cardiac repolarization, indicated by prolonged QT interval, may cause critical ventricular arrhythmias. Many anesthetics increase the QT interval by blockade of rapidly acting potassium rectifier channels. Although xenon does not affect these channels in isolated cardiomyocytes, the authors hypothesized that xenon increases the QT interval by direct and/or indirect sympathomimetic effects. Thus, the authors tested the hypothesis that xenon alters the heart rate-corrected cardiac QT (QTc) interval in anesthetic concentrations. The effect of xenon on the QTc interval was evaluated in eight healthy volunteers and in 35 patients undergoing abdominal or trauma surgery. The QTc interval was recorded on subjects in awake state, after their denitrogenation, and during xenon monoanesthesia (FetXe > 0.65). In patients, the QTc interval was recorded while awake, after anesthesia induction with propofol and remifentanil, and during steady state of xenon/remifentanil anesthesia (FetXe > 0.65). The QTc interval was determined from three consecutive cardiac intervals on electrocardiogram printouts in a blinded manner and corrected with Bazett formula. In healthy volunteers, xenon did not alter the QTc interval (mean difference: +0.11 ms [95% CI, -22.4 to 22.7]). In patients, after anesthesia induction with propofol/remifentanil, no alteration of QTc interval was noted. After propofol was replaced with xenon, the QTc interval remained unaffected (417 ± 32 ms vs. awake: 414 ± 25 ms) with a mean difference of 4.4 ms (95% CI, -4.6 to 13.5). Xenon monoanesthesia in healthy volunteers and xenon/remifentanil anesthesia in patients without clinically relevant cardiovascular disease do not increase QTc interval.

A thorough QT study to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine and escitalopram, in healthy volunteers.

PubMed

Kim, Anhye; Lim, Kyoung Soo; Lee, Howard; Chung, Hyewon; Yoon, Seo Hyun; Yu, Kyung-Sang; Cho, Joo-Youn; Jang, In-Jin; Chung, Jae-Yong

2016-07-01

Prolongation of the QT interval on an ECG is a surrogate marker for predicting the proarrhythmic potential of a drug under development. The aim of this study was to evaluate the QTc prolongation potential of two neuropsychiatric drugs, quetiapine immediate release (IR) and escitalopram, in healthy individuals. This was a randomized, open-label, 4×4 Williams crossover study, with four single-dose treatments [placebo, 400 mg moxifloxacin (positive control), 20 mg escitalopram, and 100 mg quetiapine IR], conducted in 40 healthy volunteers. Serial blood samples for pharmacokinetics and ECG were collected. Individually, RR-corrected QTc intervals (QTcI) and placebo-adjusted changes from baseline values of QTcI (ΔΔQTcI) were evaluated. Lower-bound values of the one-sided 95% confidence interval for ΔΔQTcI of moxifloxacin with more than 5 ms confirmed the sensitivity of the assay. The maximum upper bound 95% confidence interval for the ΔΔQTcI of quetiapine IR and escitalopram was 13.7 and 10.5 ms, with mean estimates of 10.2 and 6.9 ms, respectively. Peak effects of moxifloxacin and quetiapine IR on ΔΔQTcI were observed at approximately time to maximum concentration (Tmax), whereas that of escitalopram was observed 3 h after Tmax. The concentration-ΔΔQTcI relationships of quetiapine IR and escitalopram were relatively flat, as compared with that of moxifloxacin. The results demonstrated the validity of trial methodology and that quetiapine IR and escitalopram caused QT prolongation in healthy individuals. In addition, hysteresis of escitalopram-induced QTc prolongation. These results indicate that higher doses of these drugs could lead to greater QT prolongation in a dose-response manner.

Substitution of (R,S)-methadone by (R)-methadone: Impact on QTc interval.

PubMed

Ansermot, Nicolas; Albayrak, Ozgür; Schläpfer, Jürg; Crettol, Séverine; Croquette-Krokar, Marina; Bourquin, Michel; Déglon, Jean-Jacques; Faouzi, Mohamed; Scherbaum, Norbert; Eap, Chin B

2010-03-22

Methadone is administered as a chiral mixture of (R,S)-methadone. The opioid effect is mainly mediated by (R)-methadone, whereas (S)-methadone blocks the human ether-à-go-go-related gene (hERG) voltage-gated potassium channel more potently, which can cause drug-induced long QT syndrome, leading to potentially lethal ventricular tachyarrhythmias. To investigate whether substitution of (R,S)-methadone by (R)-methadone could reduce the corrected QT (QTc) interval, (R,S)-methadone was replaced by (R)-methadone (half-dose) in 39 opioid-dependent patients receiving maintenance treatment for 14 days. (R)-methadone was then replaced by the initial dose of (R,S)-methadone for 14 days (n = 29). Trough (R)-methadone and (S)-methadone plasma levels and electrocardiogram measurements were taken. The Fridericia-corrected QT (QTcF) interval decreased when (R,S)-methadone was replaced by a half-dose of (R)-methadone; the median (interquartile range [IQR]) values were 423 (398-440) milliseconds (ms) and 412 (395-431) ms (P = .06) at days 0 and 14, respectively. Using a univariate mixed-effect linear model, the QTcF value decreased by a mean of -3.9 ms (95% confidence interval [CI], -7.7 to -0.2) per week (P = .04). The QTcF value increased when (R)-methadone was replaced by the initial dose of (R,S)-methadone for 14 days; median (IQR) values were 424 (398-436) ms and 424 (412-443) ms (P = .01) at days 14 and 28, respectively. The univariate model showed that the QTcF value increased by a mean of 4.7 ms (95% CI, 1.3-8.1) per week (P = .006). Substitution of (R,S)-methadone by (R)-methadone reduces the QTc interval value. A safer cardiac profile of (R)-methadone is in agreement with previous in vitro and pharmacogenetic studies. If the present results are confirmed by larger studies, (R)-methadone should be prescribed instead of (R,S)-methadone to reduce the risk of cardiac toxic effects and sudden death.

Effects of bilastine on T-wave morphology and the QTc interval: a randomized, double-blind, placebo-controlled, thorough QTc study.

PubMed

Graff, Claus; Struijk, Johannes J; Kanters, Jørgen K; Andersen, Mads P; Toft, Egon; Tyl, Benoît

2012-05-01

The International Conference of Harmonisation (ICH) E14 guideline for thorough QT studies requires assessing the propensity of new non-antiarrhythmic drugs to affect cardiac repolarization. The present study investigates whether a composite ECG measure of T-wave morphology (Morphology Combination Score [MCS]) can be used together with the heart rate corrected QT interval (QTc) in a fully ICH E14-compliant thorough QT study to exclude clinically relevant repolarization effects of bilastine, a novel antihistamine. Thirty participants in this crossover study were randomly assigned to receive placebo, moxifloxacin 400 mg, bilastine at therapeutic and supratherapeutic doses (20 and 100 mg) and bilastine 20 mg co-administered with ketoconazole 400 mg. Resting ECGs recorded at 12 nominal time points before and after treatments were used to determine Fridericia corrected QTc (QTcF) and MCS from the T-wave characteristics: asymmetry, flatness and notching. There were no effects of bilastine monotherapy (20 and 100 mg) on MCS or QTcF at those study times where the bilastine plasma concentrations were highest. MCS changes for bilastine monotherapy did not exceed the normal intrasubject variance of T-wave shapes for triplicate ECG recordings. Maximum QTcF prolongation for bilastine monotherapy was 5 ms or less: 3.8 ms (90% CI 0.3, 7.3 ms) for bilastine 20 mg and 5.0 ms (90% CI 2.0, 8.0 ms) for bilastine 100 mg. There were no indications of bilastine inducing larger repolarization effects on T-wave morphology as compared with the QTcF interval, as evidenced by the similarity of z-score equivalents for placebo-corrected changes in MCS and QTcF values. This study shows that bilastine, at therapeutic and supratherapeutic dosages, does not induce any effects on T-wave morphology or QTcF. These results confirm the absence of an effect for bilastine on cardiac repolarization.

Tp-e interval and Tp-e/QT ratio in patients with celiac disease.

PubMed

Demirtaş, K; Yayla, Ç; Yüksel, M; Açar, B; Ünal, S; Ertem, A G; Kaplan, M; Akpinar, M Y; Kiliç, Z M Y; Kayaçetin, E

2017-11-01

Celiac disease is a chronic immune-mediated disease of the small intestine. It has been known that dilated cardiomyopathy and ischemic coronary artery disease have become more frequent in patients with celiac disease. The aim of the study was to assess Tp-e interval and Tp-e/QT ratio in patients with celiac disease. This study was conducted at a single center in collaboration with gastroenterology and cardiology clinics. Between January 2014 and June 2015, a total of 76 consecutive patients were enrolled (38 patients with celiac disease and 38 control subjects). Tp-e interval, Tp-e/QT and Tp-e/QTc ratio were measured from the 12-lead electrocardiogram. Tp-e interval (64.2±11.0 vs. 44.5±6.0; p<0.001), Tp-e/QT ratio (0.18±0.02 vs. 0.13±0.02; p<0.001) and Tp-e/QTc ratio (0.16±0.02 vs. 0.11±0.01; p<0.001) were significantly higher in patients with celiac disease than control subjects. There was a significant positive correlation between Tp-e/QTc ratio and disease duration in patients with celiac disease (r=0.480, p=0.003) and also there was a significant positive correlation between Tp-e/QTc ratio and erythrocyte sedimentation rate (r=0.434, p<0.001). Our study showed that Tp-e interval, Tp-e/QT and Tp-e/QTc ratios were increased in patients with celiac disease. Whether these changes increase the risk of ventricular arrhythmia deserve further studies. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Sex Differences in the Effect of Atomoxetine on the QT Interval in Adult Patients With Attention-Deficit Hyperactivity Disorder.

PubMed

Suzuki, Yutaro; Tajiri, Misuzu; Sugimoto, Atsunori; Orime, Naoki; Hayashi, Taketsugu; Egawa, Jun; Sugai, Takuro; Inoue, Yoshimasa; Someya, Toshiyuki

2017-02-01

The effects of atomoxetine on QT in adults remain unclear. In this study, we examined whether the use of atomoxetine to treat attention-deficit hyperactivity disorder in adults is associated with QT prolongation. Forty-one subjects with attention-deficit hyperactivity disorder were enrolled in this study. Participants were administered 40, 80, or 120 mg atomoxetine daily and were maintained on their respective dose for at least 2 weeks. We conducted electrocardiographic measurements and blood tests, measuring plasma atomoxetine concentrations after treatment. Electrocardiograms of 24 of the patients were also obtained before atomoxetine treatment. The QT interval was corrected using Bazett (QTcB) and Fridericia (QTcF) correction formulas. In these 24 patients, only the female patients had prolonged QTcB (P = 0.039) after atomoxetine treatment. There was no correlation between plasma atomoxetine concentrations and the corrected QT interval (QTc), or between atomoxetine dosage and the QTc. However, in female patients, there was a significant positive correlation between atomoxetine dosage and the QTcB (r = 0.631, P = 0.012), and there was a marginally significant positive correlation between atomoxetine dosage and the QTcF (r = 0.504, P = 0.055). In male patients, there was no correlation between atomoxetine dosage and the QTcB or QTcF intervals. There was no correlation between plasma atomoxetine concentrations and the QTc in either female or male patients. Clinicians should exhibit caution when prescribing atomoxetine, particularly for female patients.

Long-Duration Space Flight Provokes Pathologic Q-Tc Interval Prolongation

NASA Technical Reports Server (NTRS)

D'Aunno, DOminick S.; Dougherty, Anne H.; DeBlock, Heidi F.; Meck, Janice V.

2002-01-01

Space flight has a profound influence on the cardiovascular and autonomic nervous systems. Alterations in baroreflex function, plasma catecholamine concentrations, and arterial pressure regulation have been observed. Changes in autonomic regulation of cardiac function may lead to serious rhythm disturbances. In fact, ventricular tachycardia has been reported during long-duration space flight. The study aim was to determine the effects of space flight on cardiac conduction. Methods and Results: Electrocardiograms (ECGs) and serum electrolytes were obtained before and after short-duration (SD) (4-16 days) and long-duration (LD) (4-6 months) missions. Holter recordings were obtained from 3 different subjects before, during and after a 4-month mission. P-R, R-R, and Q-T intervals were measured manually in a random, blinded fashion and Bazzet's formula used to correct the Q-T interval (Q-Tc). Space flight had no clinically significant effect on electrolyte concentrations. P-R and RR intervals were decreased after SD flight (p<0.05) and recovered 3 days after landing. In the same subjects, P-R and Q-Tc intervals were prolonged after LD flight (p<0.01). Clinically significant Q-Tc prolongation (>0.44 sec) occurred during the first month of flight and persisted until 3 days after landing (p<0.01). Conclusions - Space flight alters cardiac conduction with more ominous changes seen with LD missions. Alterations in autonomic tone may explain ECG changes associated with space flight. Primary cardiac changes may also contribute to the conduction changes with LD flight. Q-Tc prolongation may predispose astronauts to ventricular arrhythmias during and after long-duration space flight.

The Half RR Rule: A Poor Rule of Thumb and Not a Risk Assessment Tool for QT Interval Prolongation.

PubMed

Berling, Ingrid; Isbister, Geoffrey K

2015-10-01

Measuring the QT interval on an electrocardiogram (ECG) is integral to risk assessment of Torsade de Pointes (TdP). This study aimed to investigate the accuracy of the 1/2 RR rule as a risk assessment tool for drug-induced TdP, comparing it to the QT nomogram, Bazett's corrected QT (QTcB), and Fridericia's corrected QT (QTcF). The authors calculated sensitivity and specificity of the 1/2 RR rule using a published data set of 129 cases of drug-induced TdP and 316 controls (noncardiotoxic overdoses), compared to the QT nomogram, QTcB > 500 msec and QTcF > 500 msec. To further determine the value of the 1/2 RR rule, its observed positive, and negative agreement were calculated when compared to the QT nomogram for determining an abnormal QT in eight samples of different drugs in overdose. The sensitivity and specificity of the 1/2 RR rule were 88% (95% confidence interval [CI] = 80% to 93%) and 53% (95% CI = 47% to 58%), respectively, compared to the QT nomogram (sensitivity = 97%, 95% CI = 92% to 99%; specificity = 99%, 95% CI = 97% to 100%). It was also less sensitive than QTcB > 500 msec and had a lower specificity than QTcB > 500 msec and QTcF > 500 msec. In drug overdose patients, the 1/2 RR rule had poor observed agreement averaging 41%, which was mainly due to poor positive agreement, except for amisulpride where there was good agreement. The 1/2 RR rule was not as sensitive as the QT nomogram or QTcB > 500 msec for drug-induced TdP. It had poor positive agreement in almost all overdose patients, resulting in over half of patients receiving unnecessary cardiac monitoring and repeat ECGs. © 2015 by the Society for Academic Emergency Medicine.

Ibrutinib does not prolong the corrected QT interval in healthy subjects: results from a thorough QT study.

PubMed

de Jong, Jan; Hellemans, Peter; Jiao, James Juhui; Huang, Yuhan; Mesens, Sofie; Sukbuntherng, Juthamas; Ouellet, Daniele

2017-12-01

Ibrutinib is an orally administered, irreversible Bruton's tyrosine kinase inhibitor for treatment of B-cell malignancy. This study evaluated the effects of single-dose ibrutinib at therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. Part 1 used an open-label, two-period sequential design to assess the safety and pharmacokinetics of single doses of ibrutinib 840 and 1680 mg in eight subjects. Part 2 was a randomized, placebo- and positive (moxifloxacin)-controlled, double-blind, single dose, four-way cross-over study to assess the effect of ibrutinib (840 and 1680 mg) on QT/QTc interval. 64 healthy subjects were planned to be enrolled. Baseline-adjusted QT (QTc) intervals for ibrutinib and moxifloxacin (assay sensitivity) were compared to placebo using linear mixed-effect model. A concentration-QTc analysis was also conducted. No clinically relevant safety observations were noted in Part 1. During Part 2, one subject experienced Grade 4 ALT/AST elevations with ibrutinib 1680 mg, leading to study termination and limiting the enrollment to 20 subjects. Ibrutinib demonstrated dose-dependent increases in exposure. The upper bounds of the 90% CIs for the mean difference in change from baseline in QTc between ibrutinib and placebo were < 10 ms at all timepoints and at supratherapeutic C max . Moxifloxacin showed the anticipated QTc effect, confirming assay sensitivity despite the early study termination. Ibrutinib caused a concentration-dependent mild shortening of QTc and mild PR prolongation, but these effects were not considered clinically meaningful. Therapeutic and supratherapeutic concentrations of ibrutinib do not prolong the QTc interval. CLINICALTRIALS.GOV: NCT02271438.

QT interval prolongation associated with sibutramine treatment

PubMed Central

Harrison-Woolrych, Mira; Clark, David W J; Hill, Geraldine R; Rees, Mark I; Skinner, Jonathan R

2006-01-01

Aims To investigate a possible association of sibutramine with QT interval prolongation. Methods Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Programme (IMMP) identified a case of QT prolongation and associated cardiac arrest in a patient taking sibutramine for 25 days. This patient was further investigated, including genotyping for long QT syndrome. Other IMMP case reports suggesting arrhythmias associated with sibutramine were assessed and further reports were obtained from the World Health Organisation (WHO) adverse drug reactions database. Results The index case displayed a novel mutation in a cardiac potassium channel subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase susceptibility to long QT intervals. Assessment of further IMMP reports identified five additional patients who experienced palpitations associated with syncope or presyncopal symptoms, one of whom had a QTc at the upper limit of normal. Assessment of reports from the WHO database identified three reports of QT prolongation and one fatal case of torsade de pointes in a patient also taking cisapride. Conclusions This case series suggests that sibutramine may be associated with QT prolongation and related dysrhythmias. Further studies are required, but in the meantime we would recommend that sibutramine should be avoided in patients with long QT syndrome and in patients taking other medicines that may prolong the QT interval. PMID:16542208

Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation

PubMed Central

Chain, Anne SY; Dubois, Vincent FS; Danhof, Meindert; Sturkenboom, Miriam CJM; Della Pasqua, Oscar

2013-01-01

Aims Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin. Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ≥10 ms was used to explore the probability of prolongation after drug administration. Results A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ≥10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. Conclusions Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ≥10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule. PMID:23351036

QTc prolongation after brain surgery.

PubMed

Capparelli, Federico J; Abello, Mauricio; Patricio Maskin, L; Arista, Eugenia; Hlavnicka, Alejandro; Diaz, Maria Fernanda; Varela, Daniel; Wainsztein, Nestor A

2013-03-01

Abnormalities observed in the electrocardiogram (ECG) after acute central nervous system (CNS) events have been reported. Our objective was to assess the incidence of heart rate-corrected QT interval (QTc) prolongation in patients admitted to the intensive care unit (ICU) after brain surgery. Admission standard 12-lead ECGs were analyzed blinded to patient data. The QT interval was measured and Bazzett's formula was used to obtain QTc. Prolonged QTc was defined as ≧450 ms. We included 114 patients in the study. The mean age was 49±17 years. Brain neoplasm was the surgical indication in 90% of the patients. The mean QTc was 470±42 ms. Prolonged QTc was found in 71% patients. The heart rate-corrected QT interval was between 450 ms and 500 ms in 52% and >500 ms in 19% of the patients. The heart rate and concentration of serum glucose were higher in the prolonged QTc group. Only 7·5% of all patients had hypokalemia (≤3 mEq/l). In the prolonged QTc group 9·2% had hypokalemia compared to 3·2% in normal QTc patients (P = 0·406). There were no significant associations between categories of QTc and the serum levels of creatinine, magnesium, calcium, sodium, or pH. Phenytoin and metoclopramide were not frequently used in patients with prolonged QTc. This study supports our hypothesis that prolonged QTc is frequently observed after a brain surgery. Hypokalemia, hypocalcaemia, and drugs such as metoclopramide or phenytoin could not explain the high incidence of prolonged QTc. Brain injury during a surgical procedure may be one of the primary causes of QTc prolongation after neurosurgery.

QTc abnormalities in deliberate self-poisoning with moclobemide.

PubMed

Downes, M A; Whyte, I M; Isbister, G K

2005-07-01

Several medications have been found to prolong the QT interval in overdose. This can predispose to torsade de pointes-type ventricular tachycardia. To analyse the effects of moclobemide deliberate self-poisoning on the length of both QT and corrected QT (QTc) intervals. Electrocardiograms (ECG) of all patients presenting to a regional toxicology service with moclobemide ingestion were reviewed. Cases where a cardiotoxic agent was coingested were excluded. QT and QTc parameters were compared with a comparison group of patients ingesting paracetamol or benzodiazepines. Of 75 patients where ECG were available, the median ingested dose was 4.5 g (interquartile range (IQR): 2.4-7.5; range: 0.6-18 g) and the median age was 34 years (IQR: 26-44). The mean QT interval was 415 ms (standard deviation (SD): 51 ms) with a mean QTc of 459 ms (SD: 44 ms), and were prolonged compared with the comparison group. Twelve female patients had a QTc > 500 ms and in seven of these causality was established based on a pre- or post-ECG with a QTc < 500 ms. Only 10% of the moclobemide cases had a heart rate (HR) > 100 beats per minute, making overcorrection of HR by Bazett's formula an unlikely cause of the findings. No cardiac arrythmias were observed other than one case of first-degree heart block. Moclobemide prolongs the QT and QTc intervals in overdose and a 12-lead ECG should be done on all moclobemide deliberate self-poisonings. Continuous cardiac monitoring for what is otherwise a relatively benign overdose would appear to be an inappropriate use of resources but can be considered in patients with a QTc > 500 ms or with known risks for QT prolongation.

No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.

PubMed

Yu, Rosie Z; Gunawan, Rudy; Li, Zhaoyang; Mittleman, Robert S; Mahmood, Asif; Grundy, John S; Singleton, Walter; Geary, Richard; Wang, Yanfeng

2016-03-01

The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects. In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis. In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively. Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.

Association of low-moderate urine arsenic and QT interval: Cross-sectional and longitudinal evidence from the Strong Heart Study.

PubMed

Moon, Katherine A; Zhang, Yiyi; Guallar, Eliseo; Francesconi, Kevin A; Goessler, Walter; Umans, Jason G; Best, Lyle G; Howard, Barbara V; Devereux, Richard B; Okin, Peter M; Navas-Acien, Ana

2018-05-21

Epidemiologic studies suggest that chronic exposure to arsenic is related to cardiovascular disease (CVD), but the pathophysiological link remains uncertain. We evaluated the association of chronic low-moderate arsenic exposure and arsenic metabolism with baseline difference and annual change in ECG measures (QT interval, JT interval, PR interval, QRS duration, and QT dispersion) using linear mixed models in the Strong Heart Study main cohort (N = 1174, median age 55 years) and family study (N = 1695 diabetes-free, median age 36 years). At baseline, arsenic exposure was measured as the sum of inorganic and methylated species in urine (ΣAs) and arsenic metabolism was measured as the relative percentage of arsenic species. Median ΣAs and Bazett heart rate-corrected QT interval (QTc) were 8.6 μg/g creatinine and 424 ms in the main cohort and 4.3 μg/g and 414 ms in the family study, respectively. In the main cohort, a comparison of the highest to lowest ΣAs quartile (>14.4 vs. <5.2 μg/g creatinine) was associated with a 5.3 (95% CI: 1.2, 9.5) ms higher mean baseline QTc interval but no difference in annual change in QTc interval. In the family study, a comparison of the highest to lowest quartile (>7.1 vs. <2.9 μg/g creatinine) was associated with a 3.2 (95% CI: 0.6, 5.7) ms higher baseline QTc interval and a 0.6 (95% CI: 0.04, 1.2) ms larger annual increase in QTc interval. Associations with JTc interval were similar but stronger in magnitude compared to QTc interval. Arsenic exposure was largely not associated with PR interval, QRS duration or QT dispersion. Similar to arsenic exposure, a pattern of lower %MMA and higher %DMA was associated with longer baseline QTc interval in both cohorts and with a larger annual change in QTc interval in the family study. Chronic low-moderate arsenic exposure and arsenic metabolism were associated with prolonged ventricular repolarization. Copyright © 2018 Elsevier Ltd. All rights reserved.

Relationships between QT interval and heart rate variability at rest and the covariates in healthy young adults.

PubMed

Arai, Kaori; Nakagawa, Yui; Iwata, Toyoto; Horiguchi, Hyogo; Murata, Katsuyuki

2013-01-01

To clarify the links between ECG QT-related parameters and heart rate variability (HRV) and the covariates possibly distorting them, the averaged RR and QT intervals in a single lead ECG were measured for 64 male and 86 female subjects aged 18-26. The QT index, defined by Rautaharju et al., in the young adults was not significantly related to any HRV parameters nor heart rate, but the Bazett's corrected QT (QTc) interval was associated negatively with the parasympathetic activity and positively with heart rate. No significant differences in the QTc interval, QT index or heart rate were seen between the men and women, but they significantly differed between both sexes after adjustment for possible covariates such as age and body mass index (BMI). Significant sex differences in parasympathetic parameters of the HRV were unchanged before and after the adjustment, but significant differences observed in the unadjusted sympathetic parameters disappeared after adjusting for covariates. Age, BMI and body fat percentage also were significant covariates affecting these ECG parameters. Consequently, QT index, unaffected by heart rate and HRV parameters, appears to be a more useful indicator than the QTc interval. Instead, the QT index and HRV parameters are recommended to be simultaneously measured in epidemiological research because they are probably complementary in assessing autonomic nervous function. Also, these parameters should be analyzed in men and women separately. Copyright © 2012 Elsevier B.V. All rights reserved.

QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.

PubMed

Wedam, Erich F; Bigelow, George E; Johnson, Rolley E; Nuzzo, Paul A; Haigney, Mark C P

2007-12-10

Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go-related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects. We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ radical R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds. Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P < .001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7-67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P < .001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group

The effects of intravenous anesthetics on QT interval during anesthetic induction with sevoflurane.

PubMed

Terao, Yoshiaki; Higashijima, Ushio; Toyoda, Tomomi; Ichinomiya, Taiga; Fukusaki, Makoto; Hara, Tetsuya

2016-12-01

Sevoflurane is known to prolong the QT interval. This study aimed to determine the effect of the interaction between intravenous anesthetics and sevoflurane on the QT interval. The study included 48 patients who underwent lumbar spine surgery. Patients received 3 μg/kg fentanyl and were then randomly allocated to either Group T, in which they received 5 mg/kg thiamylal, or Group P, in which they received 1.5 mg/kg propofol, at 2 min after administration of fentanyl injection for anesthetic induction. Vecuronium (1.5 mg/kg) and sevoflurane (3 % inhaled concentration) were administered immediately after loss of consciousness and tracheal intubation was performed 3 min after vecuronium injection. Heart rate (HR), mean arterial pressure (MAP), bispectral index score (BIS), and the heart rate-corrected QT (QTc) interval on a 12-lead electrocardiogram were recorded immediately before fentanyl administration (T1), 2 min after fentanyl injection (T2), immediately before intubation (T3), and 2 min after intubation (T4). There were no significant differences between the two groups in baseline patient characteristics. BIS and MAP significantly decreased after anesthesia induction in both groups. At T3, MAP in Group T was higher than in Group P, while HR had reduced in both groups. The QTc interval was prolonged after anesthesia induction in Group T, but did not change at any time point in Group P. The QTc interval after anesthesia induction in Group T was longer than in Group P. We concluded that an injection of propofol could counteract QTc interval prolongation associated with sevoflurane anesthesia induction.

Is prolongation of corrected QT interval associated with seizures induced by electroconvulsive therapy reduced by atropine sulfate?

PubMed

Suzuki, Yoko; Miyajima, Miho; Ohta, Katsuya; Yoshida, Noriko; Omoya, Rie; Fujiwara, Mayo; Watanabe, Takafumi; Okumura, Masaki; Yamazaki, Hiroaki; Shintaku, Masayuki; Murata, Issei; Ozaki, Shigeru; Sasaki, Takeshi; Nakamura, Mitsuru; Suwa, Hiroshi; Sasano, Tetsuo; Kawara, Tokuhiro; Matsuura, Masato; Matsushima, Eisuke

2017-11-01

Electrocardiogram abnormalities have been reported during electroconvulsive therapy (ECT). A corrected QT interval (QTc) prolongation indicates delayed ventricular repolarization, which can trigger ventricular arrhythmias such as torsade de pointes (TdP). We examined the QTc changes during generalized tonic-clonic seizures induced by ECT, and the effects of atropine sulfate on these QTc changes. We analyzed heart rate, QT interval, and QTc in 32 patients with depression who underwent ECT (25 women, 67.4 ± 8.7 years of age). The QTc from -30 to 0 seconds prestimulation was used as baseline, which was compared with QTc at 20-30 seconds and 140-150 seconds poststimulus onset. QTc was significantly prolonged at 20-30 seconds poststimulus, then significantly decreased at 140-150 seconds poststimulus, compared with baseline. QTc prolongation induced by ECT was significantly decreased by atropine sulfate. These data suggest that the risk of TdP may be enhanced by ECT. Further, the risk of cardiac ventricular arrhythmias, including TdP, may be reduced by administration of atropine sulfate. © 2017 Wiley Periodicals, Inc.

The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction.

PubMed

van der Linde, H J; Van Deuren, B; Teisman, A; Towart, R; Gallacher, D J

2008-08-01

Body core temperature (Tc) changes affect the QT interval, but correction for this has not been systematically investigated. It may be important to correct QT intervals for drug-induced changes in Tc. Anaesthetized beagle dogs were artificially cooled (34.2 degrees C) or warmed (42.1 degrees C). The relationship between corrected QT intervals (QTcV; QT interval corrected according to the Van de Water formula) and Tc was analysed. This relationship was also examined in conscious dogs where Tc was increased by exercise. When QTcV intervals were plotted against changes in Tc, linear correlations were observed in all individual dogs. The slopes did not significantly differ between cooling (-14.85+/-2.08) or heating (-13.12+/-3.46) protocols. We propose a correction formula to compensate for the influence of Tc changes and standardize the QTcV duration to 37.5 degrees C: QTcVcT (QTcV corrected for changes in core temperature)=QTcV-14 (37.5 - Tc). Furthermore, cooled dogs were re-warmed (from 34.2 to 40.0 degrees C) and marked QTcV shortening (-29%) was induced. After Tc correction, using the above formula, this decrease was abolished. In these re-warmed dogs, we observed significant increases in T-wave amplitude and in serum [K(+)] levels. No arrhythmias or increase in pro-arrhythmic biomarkers were observed. In exercising dogs, the above formula completely compensated QTcV for the temperature increase. This study shows the importance of correcting QTcV intervals for changes in Tc, to avoid misleading interpretations of apparent QTcV interval changes. We recommend that all ICH S7A, conscious animal safety studies should routinely measure core body temperature and correct QTcV appropriately, if body temperature and heart rate changes are observed.

QT Interval Prolongation and QRS Voltage Reduction in Patients with Liver Cirrhosis.

PubMed

Cichoż-Lach, Halina; Tomaszewski, Michał; Kowalik, Agnieszka; Lis, Emilia; Tomaszewski, Andrzej; Lach, Tomasz; Boczkowska, Sylwia; Celiński, Krzysztof

2015-01-01

Liver cirrhosis is associated with functional abnormalities of the cardiovascular system with co-existing electrocardiographic (ECG) abnormalities. The aim was to analyze ECG changes in patients with cirrhosis, to evaluate whether alcoholic etiology of cirrhosis and ascites has an impact on ECG changes. The study involved 81 patients with previously untreated alcoholic cirrhosis (64 patients with ascites, classes B and C according to the Child-Pugh classification; and 17 without ascites, categorized as class A); 41 patients with previously untreated cirrhosis due to chronic hepatitis C (HCV--30 patients with ascites, classes B and C; and 11 without ascites, class A); 42 with alcoholic steatohepatitis and 46 with alcoholic steatosis. The control group consisted of 32 healthy volunteers. Twelve-lead ECG recordings were performed and selected parameters were measured. Significantly longer QT and QTc intervals and lower QRS voltage were found in patients with alcoholic and HCV cirrhosis compared to the controls. Significantly lower QRS voltage was found in subjects with ascites than in those without ascites. Removal of ascites significantly increased QRS voltage. In cirrhosis, irrespective of etiology, ECG changes involved prolonged QT and QTc intervals and reduced QRS voltage. Prolonged QT and QTc intervals were not related to the severity of cirrhosis or to the presence of ascites. However, low QRS voltage was associated with the presence of ascites. Removal of ascites reverses low QRS voltage.

The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction

PubMed Central

van der Linde, H J; Van Deuren, B; Teisman, A; Towart, R; Gallacher, D J

2008-01-01

Background and purpose: Body core temperature (Tc) changes affect the QT interval, but correction for this has not been systematically investigated. It may be important to correct QT intervals for drug-induced changes in Tc. Experimental approach: Anaesthetized beagle dogs were artificially cooled (34.2 °C) or warmed (42.1 °C). The relationship between corrected QT intervals (QTcV; QT interval corrected according to the Van de Water formula) and Tc was analysed. This relationship was also examined in conscious dogs where Tc was increased by exercise. Key results: When QTcV intervals were plotted against changes in Tc, linear correlations were observed in all individual dogs. The slopes did not significantly differ between cooling (−14.85±2.08) or heating (−13.12±3.46) protocols. We propose a correction formula to compensate for the influence of Tc changes and standardize the QTcV duration to 37.5 °C: QTcVcT (QTcV corrected for changes in core temperature)=QTcV–14 (37.5 – Tc). Furthermore, cooled dogs were re-warmed (from 34.2 to 40.0 °C) and marked QTcV shortening (−29%) was induced. After Tc correction, using the above formula, this decrease was abolished. In these re-warmed dogs, we observed significant increases in T-wave amplitude and in serum [K+] levels. No arrhythmias or increase in pro-arrhythmic biomarkers were observed. In exercising dogs, the above formula completely compensated QTcV for the temperature increase. Conclusions and implications: This study shows the importance of correcting QTcV intervals for changes in Tc, to avoid misleading interpretations of apparent QTcV interval changes. We recommend that all ICH S7A, conscious animal safety studies should routinely measure core body temperature and correct QTcV appropriately, if body temperature and heart rate changes are observed. PMID:18574451

Sample size, power calculations, and their implications for the cost of thorough studies of drug induced QT interval prolongation.

PubMed

Malik, Marek; Hnatkova, Katerina; Batchvarov, Velislav; Gang, Yi; Smetana, Peter; Camm, A John

2004-12-01

Regulatory authorities require new drugs to be investigated using a so-called "thorough QT/QTc study" to identify compounds with a potential of influencing cardiac repolarization in man. Presently drafted regulatory consensus requires these studies to be powered for the statistical detection of QTc interval changes as small as 5 ms. Since this translates into a noticeable drug development burden, strategies need to be identified allowing the size and thus the cost of thorough QT/QTc studies to be minimized. This study investigated the influence of QT and RR interval data quality and the precision of heart rate correction on the sample sizes of thorough QT/QTc studies. In 57 healthy subjects (26 women, age range 19-42 years), a total of 4,195 drug-free digital electrocardiograms (ECG) were obtained (65-84 ECGs per subject). All ECG parameters were measured manually using the most accurate approach with reconciliation of measurement differences between different cardiologists and aligning the measurements of corresponding ECG patterns. From the data derived in this measurement process, seven different levels of QT/RR data quality were obtained, ranging from the simplest approach of measuring 3 beats in one ECG lead to the most exact approach. Each of these QT/RR data-sets was processed with eight different heart rate corrections ranging from Bazett and Fridericia corrections to the individual QT/RR regression modelling with optimization of QT/RR curvature. For each combination of data quality and heart rate correction, standard deviation of individual mean QTc values and mean of individual standard deviations of QTc values were calculated and used to derive the size of thorough QT/QTc studies with an 80% power to detect 5 ms QTc changes at the significance level of 0.05. Irrespective of data quality and heart rate corrections, the necessary sample sizes of studies based on between-subject comparisons (e.g., parallel studies) are very substantial requiring >140

QT Adaptation and Intrinsic QT Variability in Congenital Long QT Syndrome.

PubMed

Seethala, Srikanth; Singh, Prabhpreet; Shusterman, Vladimir; Ribe, Margareth; Haugaa, Kristina H; Němec, Jan

2015-12-16

Increased variability of QT interval (QTV) has been linked to arrhythmias in animal experiments and multiple clinical situations. Congenital long QT syndrome (LQTS), a pure repolarization disease, may provide important information on the relationship between delayed repolarization and QTV. Twenty-four-hour Holter monitor tracings from 78 genotyped congenital LQTS patients (52 females; 51 LQT1, 23 LQT2, 2 LQT5, 2 JLN, 27 symptomatic; age, 35.2±12.3 years) were evaluated with computer-assisted annotation of RR and QT intervals. Several models of RR-QT relationship were tested in all patients. A model assuming exponential decrease of past RR interval contributions to QT duration with 60-second time constant provided the best data fit. This model was used to calculate QTc and residual "intrinsic" QTV, which cannot be explained by heart rate change. The intrinsic QTV was higher in patients with long QTc (r=0.68; P<10(-4)), and in LQT2 than in LQT1/5 patients (5.65±1.28 vs 4.46±0.82; P<0.0002). Both QTc and intrinsic QTV were similar in symptomatic and asymptomatic patients (467±52 vs 459±53 ms and 5.10±1.19 vs 4.74±1.09, respectively). In LQTS patients, QT interval adaptation to heart rate changes occurs with time constant ≈60 seconds, similar to results reported in control subjects. Intrinsic QTV correlates with the degree of repolarization delay and might reflect action potential instability observed in animal models of LQTS. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Metoprolol and diltiazem ameliorate ziprasidone-induced prolonged corrected QT interval in rats.

PubMed

Erbas, Oytun; Yilmaz, Mustafa

2015-12-01

Ziprasidone, an atypical antipsychotic agent, has been shown to increase the corrected QT (QTc) interval in some patients. The aim of this study was to reveal the effects of metoprolol and diltiazem on ziprasidone drug-induced prolonged QTc interval. A total of 24 rats were equally divided into the following four groups: the first group was used as the control and received 1 mL/kg saline; 3 mg/kg ziprasidone and saline were administered to the second group; 3 mg/kg ziprasidone and 1 mg/kg metoprolol were administered to the third group and 3 mg/kg ziprasidone and 2 mg/kg diltiazem were administered to the fourth group. Two hours following application of the drugs, the QTc was calculated by performing electrocardiography in derivation (D)I. The duration of QTc interval was compared among the four groups. The mean QTc intervals were significantly increased in the third and fourth groups compared with the second group (p < 0.0005 and p < 0.0001, respectively). The study demonstrated the effectiveness of metoprolol and diltiazem in the prevention of ziprasidone-induced elongation in the QTc interval. Both metoprolol and diltiazem may be considered in the prophylactic therapy of high-risk patients who are using ziprasidone. © The Author(s) 2013.

Effect of dexmedetomidine on the QT interval in pediatric patients undergoing general anesthesia.

PubMed

Kako, Hiromi; Krishna, Senthil G; Sebastian, Roby; Smith, Kyle; Tobias, Joseph D

2015-12-01

Recent years have seen an increase in the use of dexmedetomidine in pediatric patients presenting for surgical procedures. However, only a limited number of studies have evaluated its effects on the QT interval in this patient group. To address this lack of knowledge, we have evaluated the effects of dexmedetomidine on the QT interval in children receiving sevoflurane anesthesia. This study was a prospective case-control study in which pediatric patients presenting for anesthetic care were divided into two groups--the dexmedetomidine (D) and control (C) groups. Three electrocardiograms (ECGs) were obtained on each patient, including a baseline ECG (T1) prior to anesthetic induction and an ECG after the induction of anesthesia with sevoflurane (T2). In group D, the third ECG was obtained 2 min after the administration of dexmedetomidine, which in turn was started immediately after the T2 ECG reading (T3D); in group C, it was obtained 2 min after the T2 reading (T3C). Statistical analysis was performed using analysis of variance to compare the QT intervals at the three time points outlined above. A total of 50 patients were recruited to the study, ranging in age from 1 to 16 [mean 7.9 ± 4.1 (SD) years]. There were 25 patients in group C and 25 in group D. There were no statistical differences in the demographics between the 2 groups. In group C, the QTc was noted to increase progressively with the administration of sevoflurane (T3C vs. T1; P = 0.006). In group D, following the administration of dexmedetomidine, there was a significant decrease in the QTc relative to the post-induction value [436 ± 25 (T2) vs. 418 ± 17 ms (T3D); P < 0.01]. A progressive lengthening of the QTc interval following the administration of sevoflurane was observed in the control group. In the dexmedetomidine group, there was a significant shortening of the QTc interval following the administration of dexmedetomidine compared to the length of the post-induction QTc interval and when

QT dispersion and rate-corrected QT dispersion during electroconvulsive therapy in elderly patients.

PubMed

Yamaguchi, Shigeki; Nagao, Masaru; Ikeda, Tomohisa; Fukagawa, Daigo; Kimura, Yoshiyuki; Kitajima, Toshimitsu; Minami, Junichi

2011-09-01

Electroconvulsive therapy (ECT) induces increase of QT dispersion (QTD) and the rate-corrected QTD (QTcD), which are associated with increased risk of ventricular arrhythmias and cardiovascular mortality. The effects of electrical stimulus during ECT on QTD and QTcD in elderly patients are of considerable interest. The purpose of this study was to clarify the differential effects of electrical stimulus caused by ECT on interbeat interval, QT interval, the rate-corrected QT (QTc) interval, QTD, and the QTcD under propofol anesthesia between younger and elderly patients with major depression. Twenty younger psychiatric patients (aged 30-40 years) and 20 elderly patients (aged 65-75 years) scheduled for ECT were studied under propofol anesthesia. A 12-lead electrocardiogram was monitored to measure parameters. Muscle paralysis was achieved by administering 1-mg/kg succinylcholine intravenously, and the efficacy of ECT was determined by the tourniquet technique. The mean arterial pressure in the elderly was significantly higher than that of the younger patients from immediately to 2 minutes after electrical stimulus. The interbeat interval in the elderly was significantly lower than that of the younger patients from immediately to 1 minute after electrical stimulus. There was no statistically significant difference in the QT interval between the groups. The baseline value of QTc interval was higher than the normal limits, and the QTc interval in the elderly was significantly lower than that of the younger patients from immediately to 1 minute after electrical stimulus. The baseline value of QTD was higher than the normal limits, and the QTD in the elderly was significantly higher than that of the younger patients from immediately to 7 minutes after electrical stimulus. The baseline value of QTcD was higher than the normal limits, and the QTcD in the elderly was significantly higher than that of the younger patients from immediately to 7 minutes after electrical

QT interval correction for drug-induced changes in body temperature during integrated cardiovascular safety assessment in regulatory toxicology studies in dogs: A case study.

PubMed

El Amrani, Abdel-Ilah; El Amrani-Callens, Francine; Loriot, Stéphane; Singh, Pramila; Forster, Roy

2016-01-01

Cardiovascular safety assessment requires accurate evaluation of QT interval, which depends on the length of the cardiac cycle and also on core body temperature (BT). Increases in QT interval duration have been shown to be associated with decreases in BT in dogs. An example of altered QT interval duration associated with changes in body temperature observed during a 4-week regulatory toxicology study in dogs is presented. Four groups of Beagle dogs received the vehicle or test item once on Day 1, followed by a 4-week observation period. Electrocardiogram (ECG) parameters were continuously recorded on Days 1 and 26 by jacketed external telemetry (JET). Core body temperature (BT) was measured with a conventional rectal thermometer at appropriate time-points during the Day 1 recording period. Decreased BT was observed approximately 2h after treatment on Day 1, along with increased QT interval duration corrected according to the Van de Water formula (QTcV), but the effect was no longer observed after correction for changes in BT [QTcVcT=QTcV-14(37.5-BT)] according to the Van der Linde formula. No significant changes in QTcV were reported at the end of the observation period, on Day 26. The present study demonstrates that core body (rectal) temperature can easily be monitored at appropriate time-points during JET recording in regulatory toxicology studies in dogs, in order to correct QT interval duration values for treatment-related changes in BT. The successful application of the Van der Linde formula to correct QTc prolongation for changes in BT was demonstrated. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Comparison of corrected QT interval as measured on electroencephalography versus 12-lead electrocardiography in children with a history of syncope.

PubMed

Massey, Shavonne L; Wise, Marshall S; Madan, Nandini; Carvalho, Karen; Khurana, Divya; Legido, Agustin; Valencia, Ignacio

2011-11-01

Long QT syndrome can present with neurological manifestations, including syncope and seizure-like activity. These patients often receive an initial neurologic evaluation, including electroencephalography (EEG). Our previous retrospective study suggested an increased prevalence of prolonged corrected QT interval (QTc) measured during the EEG of patients with syncope. The aim of the current study is to assess the accuracy of the EEG QTc reading compared with the nonsimultaneous 12-lead electrocardiography (ECG) in children with syncope. Abnormal QTc was defined as ≥450 ms in boys, ≥460 ms in girls. Forty-two children were included. There was no significant correlation between QTc readings in the EEG and ECG. EEG failed to identify 2 children with prolonged QTc in the ECG and overestimated the QTc in 3 children with normal QTc in the ECG. This study suggests that interpretation of the QTc segment during an EEG is limited. Further studies with simultaneous EEG and 12-lead ECG are warranted.

Association between the physical activity and heart rate corrected-QT interval in older adults.

PubMed

Michishita, Ryoma; Fukae, Chika; Mihara, Rikako; Ikenaga, Masahiro; Morimura, Kazuhiro; Takeda, Noriko; Yamada, Yosuke; Higaki, Yasuki; Tanaka, Hiroaki; Kiyonaga, Akira

2015-07-01

Increased physical activity can reduce the incidence of cardiovascular disease and the mortality rate. In contrast, a prolonged heart rate corrected-QT (QTc) interval is associated with an increased risk of arrhythmias, sudden cardiac death and coronary artery disease. The present cross-sectional study was designed to clarify the association between the physical activity level and the QTc interval in older adults. The participants included 586 older adults (267 men and 319 women, age 71.2 ± 4.7 years) without a history of cardiovascular disease, who were taking cardioactive drugs. Electrocardiography was recorded with a standard resting 12-lead electrocardiograph, while the QTc interval was calculated according to Hodges' formula. The physical activity level was assessed using a triaxial accelerometer. The participants were divided into four categories, which were defined equally quartile distributions of the QTc interval. After adjusting for age, body mass index, waist circumference and the number of steps, the time spent in inactivity was higher and the time spent in light physical activity was significantly lower in the longest QTc interval group than in the shortest QTc interval group in both sexes (P < 0.05, respectively). However, there were no significant differences in the time spent in moderate and vigorous physical activities among the four groups in either sex. These results suggest that a decreased physical activity level, especially inactivity and light intensity physical activity, were associated with QTc interval in older adults. © 2014 Japan Geriatrics Society.

The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses

PubMed Central

Ring, Arne; Port, Andreas; Graefe-Mody, E Ulrike; Revollo, Ivette; Iovino, Mario; Dugi, Klaus A

2011-01-01

AIM To evaluate the potential effects of therapeutic and supratherapeutic doses of linagliptin (BI 1356) on the QT/QTc interval in healthy subjects. METHODS The study was a randomized, double-blind, placebo-controlled, four-period crossover study using single oral doses of linagliptin (5 mg and 100 mg), moxifloxacin (400 mg) and placebo. Electrocardiogram (ECG) profiles using triplicates of 12-lead 10-s ECGs were digitally recorded pre-dose and after drug administration. The mean change from baseline (MCfB) of the individually heart rate corrected QT interval (QTcI) between 1 and 4 h postdrug administration was the primary end point. Blood samples to measure plasma concentrations of linagliptin and its main metabolite were also obtained. RESULTS Forty-four Caucasian subjects (26 male) entered the study and 43 subjects completed the study as planned in the protocol. Linagliptin was not associated with an increase in the baseline-adjusted mean QTcI, at any time point. The placebo-corrected MCfB of QTcI was −1.1 (90% CI −2.7, 0.5) ms and −2.5 (–4.1, –0.9) ms for linagliptin 5 mg and 100 mg, respectively, thus within the non-inferiority margin of 10 ms according to ICH E14. Linagliptin was well tolerated; the assessment of ECGs and other safety parameters gave no clinically relevant findings at either dose tested. Maximum plasma concentrations after administration of 100-mg linagliptin were ∼24-fold higher than those observed previously for chronic treatment with the therapeutic 5-mg dose. Assay sensitivity was confirmed by a placebo-corrected MCfB of QTcI with moxifloxacin of 6.9 (90% CI 5.4, 8.5) ms. CONCLUSIONS Therapeutic and significantly supratherapeutic exposure to linagliptin is not associated with QT interval prolongation. PMID:21306414

Hypoglycaemia and QT interval prolongation in type 1 diabetes--bridging the gap between clamp studies and spontaneous episodes.

PubMed

Christensen, T F; Cichosz, S L; Tarnow, L; Randløv, J; Kristensen, L E; Struijk, J J; Eldrup, E; Hejlesen, O K

2014-01-01

We propose a study design with controlled hypoglycaemia induced by subcutaneous injection of insulin and matched control episodes to bridge the gap between clamp studies and studies of spontaneous hypoglycaemia. The observed prolongation of the heart rate corrected QT interval (QTc) during hypoglycaemia varies greatly between studies. We studied ten adults with type 1 diabetes (age 41±15years) without cardiovascular disease or neuropathy. Single-blinded hypoglycaemia was induced by a subcutaneous insulin bolus followed by a control episode on two occasions separated by 4weeks. QT intervals were measured using the semi-automatic tangent approach, and QTc was derived by Bazett's (QTcB) and Fridericia's (QTcF) formulas. QTcB increased from baseline to hypoglycaemia (403±20 vs. 433±39ms, p<0.001). On the euglycaemia day, QTcB also increased (398±20 vs. 410±27ms, p<0.01), but the increase was less than during hypoglycaemia (p<0.001). The same pattern was seen for QTcF. Plasma adrenaline levels increased significantly during hypoglycaemia compared to euglycaemia (p<0.01). Serum potassium levels decreased similarly after insulin injection during both hypoglycaemia and euglycaemia. Hypoglycaemia as experienced after a subcutaneous injection of insulin may cause QTc prolongation in type 1 diabetes. However, the magnitude of prolongation is less than typically reported during glucose clamp studies, possible because of the study design with focus on minimizing unwanted study effects. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of phenobarbital and levetiracetam on PR and QTc intervals in patients with post-stroke seizure.

PubMed

Siniscalchi, Antonio; Scaglione, Francesco; Sanzaro, Enzo; Iemolo, Francesco; Albertini, Giorgio; Quirino, Gianluca; Manes, Maria Teresa; Gratteri, Santo; Mercuri, Nicola Biagio; De Sarro, Giovambattista; Gallelli, Luca

2014-12-01

Sudden unexplained/unexpected death (SUDEP) is related to high mortality in patients with epilepsy. The prolongation of QT interval, involved in cardiac arrhythmia-related SUDEP, may be precipitated by antiepileptic drugs (AEDs). In this study, we evaluated the effects of phenobarbital and levetiracetam on PR-QTc intervals in patients with post-stroke seizures. We performed an open-label, parallel group, prospective, multicenter study between June 2009 and December 2013 in patients older than 18 years of age with a clinical diagnosis of post-stroke seizure and treated with phenobarbital or levetiracetam. In order to exclude a role of cerebral post-stroke injury on modulation of PR and QTc intervals, patients with cerebral post-stroke injury and without seizures were also enrolled as controls. Interictal electrocardiography analysis revealed no significant difference in PR interval between patients treated with an AED (n = 49) and control patients (n = 50) (181.25 ± 12.05 vs. 182.4 ± 10.3 ms; p > 0.05). In contrast, a significantly longer QTc interval was recorded in patients treated with an AED compared with control patients (441.2 ± 56.6 vs. 396.8 ± 49.3 ms; p < 0.01). Patients treated with phenobarbital showed a significantly longer QTc interval than patients treated with levetiracetam (460.0 ± 57.2 vs. 421.5 ± 50.1 ms; p < 0.05). The study reported that in patients with late post-stroke seizures, phenobarbital prolonged QTc interval more so than levetiracetam.

Cardiac Safety of Ozanimod, a Novel Sphingosine‐1‐Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study

PubMed Central

Hartung, Jeffrey P.; Olson, Allan D.; Mendzelevski, Boaz; Timony, Gregg A.; Boehm, Marcus F.; Peach, Robert J.; Gujrathi, Sheila; Frohna, Paul A.

2017-01-01

Abstract Ozanimod is a novel, selective, oral sphingosine‐1‐phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double‐blind, placebo‐controlled, positive‐controlled, parallel‐group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of moxifloxacin 400 mg or placebo was administered on days 2 and 17. The primary end point was the time‐matched, placebo‐corrected, baseline‐adjusted mean QTcF (ΔΔQTcF). A total of 113/124 (91.1%) subjects completed the study. The upper limits of the 2‐sided 90% confidence intervals for ΔΔQTcF for both ozanimod 1 and 2 mg were below the 10‐millisecond regulatory threshold. No QTcF >480 milliseconds or postdose change in QTcF of >60 milliseconds was observed. There was no evidence of a positive relationship between concentrations of ozanimod and its active metabolites and ΔΔQTcF. Although ozanimod blunted the observed diurnal increase in heart rate, excursions below predose heart rates were no greater than with placebo. Results demonstrate that ozanimod does not prolong the QTc interval or cause clinically significant bradycardia, supporting ozanimod's evolving favorable cardiac safety profile. PMID:28783871

Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

PubMed

Tran, Jonathan Q; Hartung, Jeffrey P; Olson, Allan D; Mendzelevski, Boaz; Timony, Gregg A; Boehm, Marcus F; Peach, Robert J; Gujrathi, Sheila; Frohna, Paul A

2018-03-01

Ozanimod is a novel, selective, oral sphingosine-1-phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double-blind, placebo-controlled, positive-controlled, parallel-group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of moxifloxacin 400 mg or placebo was administered on days 2 and 17. The primary end point was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF). A total of 113/124 (91.1%) subjects completed the study. The upper limits of the 2-sided 90% confidence intervals for ΔΔQTcF for both ozanimod 1 and 2 mg were below the 10-millisecond regulatory threshold. No QTcF >480 milliseconds or postdose change in QTcF of >60 milliseconds was observed. There was no evidence of a positive relationship between concentrations of ozanimod and its active metabolites and ΔΔQTcF. Although ozanimod blunted the observed diurnal increase in heart rate, excursions below predose heart rates were no greater than with placebo. Results demonstrate that ozanimod does not prolong the QTc interval or cause clinically significant bradycardia, supporting ozanimod's evolving favorable cardiac safety profile. © 2017 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

The sodium glucose cotransporter 2 inhibitor empagliflozin does not prolong QT interval in a thorough QT (TQT) study

PubMed Central

2013-01-01

Background Empagliflozin is a potent, selective sodium glucose cotransporter 2 (SGLT2) inhibitor in development as an oral antidiabetic treatment. This QT interval study assessed potential effects of empagliflozin on ventricular repolarisation and other electrocardiogram (ECG) parameters. Methods A randomised, placebo-controlled, single-dose, double-blind, five-period crossover study incorporating a novel double-placebo period design to reduce sample size, while maintaining full statistical power. Treatments: single empagliflozin doses of 25 mg (therapeutic) and 200 mg (supratherapeutic), matching placebo and open-label moxifloxacin 400 mg (positive control). Triplicate 12-lead ECGs of 10 second duration were recorded at baseline and during the first 24 hours after dosing. The primary endpoint was mean change from baseline (MCfB) in the population heart rate-corrected QT interval (QTcN) between 1–4 hours after dosing. Results Thirty volunteers (16 male, 14 female, mean [range] age: 34.5 [18–52] years) were randomised. The placebo-corrected MCfB in QTcN 1–4 hours after dosing was 0.6 (90% CI: -0.7, 1.9) ms and -0.2 (-1.4, 0.9) ms for empagliflozin 25 mg and 200 mg, respectively, below the ICH E14 defined threshold of regulatory concern 10 ms. Assay sensitivity was confirmed by a placebo-corrected MCfB in QTcN 2–4 hours post-dose of 12.4 (10.7, 14.1) ms with moxifloxacin 400 mg. Empagliflozin tolerability was good for all volunteers; 23.3% experienced adverse events (AEs) with empagliflozin and 27.6% with placebo. The most frequent AE was nasopharyngitis. Conclusions/interpretation Single doses of empagliflozin 25 mg and 200 mg were not associated with QTcN prolongation and were well tolerated in healthy volunteers. Trial registration ClinicalTrials.gov: NCT01195675 PMID:23617452

Translating QT interval prolongation from conscious dogs to humans.

PubMed

Dubois, Vincent F S; Smania, Giovanni; Yu, Huixin; Graf, Ramona; Chain, Anne S Y; Danhof, Meindert; Della Pasqua, Oscar

2017-02-01

In spite of screening procedures in early drug development, uncertainty remains about the propensity of new chemical entities (NCEs) to prolong the QT/QTc interval. The evaluation of proarrhythmic activity using a comprehensive in vitro proarrhythmia assay does not fully account for pharmacokinetic-pharmacodynamic (PKPD) differences in vivo. In the present study, we evaluated the correlation between drug-specific parameters describing QT interval prolongation in dogs and in humans. Using estimates of the drug-specific parameter, data on the slopes of the PKPD relationships of nine compounds with varying QT-prolonging effects (cisapride, sotalol, moxifloxacin, carabersat, GSK945237, SB237376 and GSK618334, and two anonymized NCEs) were analysed. Mean slope estimates varied between -0.98 ms μM -1 and 6.1 ms μM -1 in dogs and -10 ms μM -1 and 90 ms μM -1 in humans, indicating a wide range of effects on the QT interval. Linear regression techniques were then applied to characterize the correlation between the parameter estimates across species. For compounds without a mixed ion channel block, a correlation was observed between the drug-specific parameter in dogs and humans (y = -1.709 + 11.6x; R 2  = 0.989). These results show that per unit concentration, the drug effect on the QT interval in humans is 11.6-fold larger than in dogs. Together with information about the expected therapeutic exposure, the evidence of a correlation between the compound-specific parameter in dogs and in humans represents an opportunity for translating preclinical safety data before progression into the clinic. Whereas further investigation is required to establish the generalizability of our findings, this approach can be used with clinical trial simulations to predict the probability of QT prolongation in humans. © 2016 The British Pharmacological Society.

[Factors related to the QT prolongation in chronic renal failure].

PubMed

Kurosu, M; Ando, Y; Akimoto, T; Ono, S; Kusano, E; Asano, Y

1999-04-01

QT prolongation, a risk factor for arrhythmia and cardiac death, is observed in uremic patients. Though hypocalcemia, autonomic nerve dysfunction and cardiac hypertrophy are assumed to cause the uremic QT prolongation, the exact mechanism remains unspecified. We therefore examined factors related to the QT interval in chronic renal failure (CRF). Corrected QT interval (QTc) was significantly prolonged in CRF just before the induction of dialysis therapy (group A) compared with nephrotic syndrome with the intact or mildly impaired renal function (group B). QTc was also prolonged in acute renal failure (group C). Cardio-thoracic ratio, serum albumin and Ca correlated with QTc in group A, but not in B or C. A single HD session in group A failed to shorten QTc, despite a significant increase in serum Ca++. Autonomic dysfunction did not appear to be a major determinant of QT prolongation, since QTc was not different between diabetics and non-diabetics in group A and in chronic HD patients (group D). In group D, QTc did not correlate with SV1 + RV5 on ECG or left ventricular wall thickness (LVWT) on echocardiography. In another group of chronic HD patients (group E), there was no significant correlation between QTc and the parameters of left ventricular mass, plasma brain natriuretic peptide (BNP). However, in the patients subjected to repeated echocardiography in group D, QTc and LVWT changed in parallel. In a retrospective analysis of QTc in group D, QTc was maximally prolonged at the time of starting HD therapy, and gradually improved in the following 1-5 years in both diabetics and non-diabetics. In contrast, chronic CAPD patients (group F) revealed no improvement of QTc. Thus, uremic QT prolongation cannot be explained simply by any of the previously assumed factors, but appears to be affected by multiple factors, which are partially correctable by chronic HD therapy.

Drug-induced QT interval prolongation: does ethnicity of the thorough QT study population matter?

PubMed Central

Shah, Rashmi R

2013-01-01

Inter-ethnic differences in drug responses have been well documented. Drug-induced QT interval prolongation is a major safety concern and therefore, regulatory authorities recommend a clinical thorough QT study (TQT) to investigate new drugs for their QT-prolonging potential. A positive study, determined by breach of a preset regulatory threshold, significantly influences late phase clinical trials by requiring intense ECG monitoring. A few studies that are currently available, although not statistically conclusive at present, question the assumption that ethnicity of the study population may not influence the outcome of a TQT study. Collective consideration of available pharmacogenetic and clinical information suggests that there may be inter-ethnic differences in QT-prolonging effects of drugs and that Caucasians may be more sensitive than other populations. The information also suggest s that (a) these differences may depend on the QT-prolonging potency of the drug and (b) exposure–response (E–R) analysis may be more sensitive than simple changes in QTc interval in unmasking this difference. If the QT response in Caucasians is generally found to be more intense than in non-Caucasians, there may be significant regulatory implications for domestic acceptance of data from a TQT study conducted in foreign populations. However, each drug will warrant an individual consideration when extrapolating the results of a TQT studyfrom one ethnic population to another and the ultimate clinical relevance of any difference. Further adequately designed and powered studies, investigating the pharmacologic properties and E–R relationships of additional drugs with different potencies, are needed in Caucasians, Oriental/Asian and African populations before firm conclusions can be drawn. PMID:22882246

Interplay Between Genetic Substrate, QTc Duration, and Arrhythmia Risk in Patients With Long QT Syndrome.

PubMed

Mazzanti, Andrea; Maragna, Riccardo; Vacanti, Gaetano; Monteforte, Nicola; Bloise, Raffaella; Marino, Maira; Braghieri, Lorenzo; Gambelli, Patrick; Memmi, Mirella; Pagan, Eleonora; Morini, Massimo; Malovini, Alberto; Ortiz, Martin; Sacilotto, Luciana; Bellazzi, Riccardo; Monserrat, Lorenzo; Napolitano, Carlo; Bagnardi, Vincenzo; Priori, Silvia G

2018-04-17

Long QT syndrome (LQTS) is a common inheritable arrhythmogenic disorder, often secondary to mutations in the KCNQ1, KCNH2, and SCN5A genes. The disease is characterized by a prolonged ventricular repolarization (QTc interval) that confers susceptibility to life-threatening arrhythmic events (LAEs). This study sought to create an evidence-based risk stratification scheme to personalize the quantification of the arrhythmic risk in patients with LQTS. Data from 1,710 patients with LQTS followed up for a median of 7.1 years (interquartile range [IQR]: 2.7 to 13.4 years) were analyzed to estimate the 5-year risk of LAEs based on QTc duration and genotype and to assess the antiarrhythmic efficacy of beta-blockers. The relationship between QTc duration and risk of events was investigated by comparison of linear and cubic spline models, and the linear model provided the best fit. The 5-year risk of LAEs while patients were off therapy was then calculated in a multivariable Cox model with QTc and genotype considered as independent factors. The estimated risk of LAEs increased by 15% for every 10-ms increment of QTc duration for all genotypes. Intergenotype comparison showed that the risk for patients with LQT2 and LQT3 increased by 130% and 157% at any QTc duration versus patients with LQT1. Analysis of response to beta-blockers showed that only nadolol reduced the arrhythmic risk in all genotypes significantly compared with no therapy (hazard ratio: 0.38; 95% confidence interval: 0.15 to 0.93; p = 0.03). The study provides an estimator of risk of LAEs in LQTS that allows a granular estimate of 5-year arrhythmic risk and demonstrate the superiority of nadolol in reducing the risk of LAEs in LQTS. Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

High Resolution ECG for Evaluation of QT Interval Variability during Exposure to Acute Hypoxia

NASA Technical Reports Server (NTRS)

Zupet, P.; Finderle, Z.; Schlegel, Todd T.; Starc, V.

2010-01-01

Ventricular repolarization instability as quantified by the index of QT interval variability (QTVI) is one of the best predictors for risk of malignant ventricular arrhythmias and sudden cardiac death. Because it is difficult to appropriately monitor early signs of organ dysfunction at high altitude, we investigated whether high resolution advanced ECG (HR-ECG) analysis might be helpful as a non-invasive and easy-to-use tool for evaluating the risk of cardiac arrhythmias during exposure to acute hypoxia. 19 non-acclimatized healthy trained alpinists (age 37, 8 plus or minus 4,7 years) participated in the study. Five-minute high-resolution 12-lead electrocardiograms (ECGs) were recorded (Cardiosoft) in each subject at rest in the supine position breathing room air and then after breathing 12.5% oxygen for 30 min. For beat-to-beat RR and QT variability, the program of Starc was utilized to derive standard time domain measures such as root mean square of the successive interval difference (rMSSD) of RRV and QTV, the corrected QT interval (QTc) and the QTVI in lead II. Changes were evaluated with paired-samples t-test with p-values less than 0.05 considered statistically significant. As expected, the RR interval and its variability both decreased with increasing altitude, with p = 0.000 and p = 0.005, respectively. Significant increases were found in both the rMSSDQT and the QTVI in lead II, with p = 0.002 and p = 0.003, respectively. There was no change in QTc interval length (p = non significant). QT variability parameters may be useful for evaluating changes in ventricular repolarization caused by hypoxia. These changes might be driven by increases in sympathetic nervous system activity at ventricular level.

Scientific white paper on concentration-QTc modeling.

PubMed

Garnett, Christine; Bonate, Peter L; Dang, Qianyu; Ferber, Georg; Huang, Dalong; Liu, Jiang; Mehrotra, Devan; Riley, Steve; Sager, Philip; Tornoe, Christoffer; Wang, Yaning

2018-06-01

The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies. Topics included are: important study design features in a phase 1 study; modeling objectives and approach; exploratory plots; the pre-specified linear mixed effects model; general principles for model development and evaluation; and expectations for modeling analysis plans and reports. The recommendations are based on current best modeling practices, scientific literature and personal experiences of the authors. These recommendations are expected to evolve as their implementation during drug development provides additional data and with advances in analytical methodology.

Influence of gender and types of sports training on QT variables in young elite athletes.

PubMed

Omiya, Kazuto; Sekizuka, Hiromitsu; Kida, Keisuke; Suzuki, Kengo; Akashi, Yoshihiro J; Ohba, Haruo; Musha, Haruki

2014-01-01

Influence of gender and sports training on QT variables such as QT interval and dispersion (QT dispersion: QTD) in young elite athletes were evaluated. Subjects included 104 male and 97 female Japanese elite athletes (mean age 21.6 years). Sports included basketball, fencing, gymnastics, judo, swimming, tennis, track and field and volleyball. Age-matched healthy non-athletes (32 men and 20 women) were enrolled as controls. QT measurements were manually obtained from a 12-lead resting electrocardiogram and QTD was calculated as the difference between the longest and shortest QT intervals. A corrected QT interval (QTc) was obtained using Bazett's formula. Subjects were divided into two groups; an endurance training group and a static training group on the basis of their training types. Maximum and minimum QTc were significantly longer in female athletes than in male athletes (max: 414.2 vs. 404.5 ms, min: 375.1 vs. 359.2 ms, p<0.0001 respectively), whereas QTc dispersion (QTcD) was shorter in female athletes than in male athletes (39.2 vs. 45.3 ms, p<0.0001). QTcD was significantly shorter in female athletes than in the female control group (39.2 vs. 45.2 ms, p<0.05). However, no statistically significant difference was observed between male athletes and the male control group. Male gymnasts exhibited significantly longer QTcD than the control group (p<0.01), but female gymnasts had significantly shorter QTcD than the control group (p<0.05). Maximum QTc intervals were prolonged in the male static training group compared with non-athletes, and QTcDs in the static training group were prolonged compared with the endurance training group. However, no significant difference was observed in the female group. In conclusion, both gender and different characteristics of sports training may affect QT variables even in young elite athletes. Vigorous static exercise training may independently prolong QT variables.

A Multiple-Dose, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group QT/QTc Study to Evaluate the Electrophysiologic Effects of THC/CBD Spray.

PubMed

Sellers, Edward M; Schoedel, Kerri; Bartlett, Cindy; Romach, Myroslava; Russo, Ethan B; Stott, Colin G; Wright, Stephen; White, Linda; Duncombe, Paul; Chen, Chien-Feng

2013-07-01

Delta-9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray has proved efficacious in the treatment of spasticity in multiple sclerosis and chronic pain. A thorough QT/QTc study was performed to investigate the effects of THC/CBD spray on electrocardiogram (ECG) parameters in compliance with regulatory requirements, evaluating the effect of a recommended daily dose (8 sprays/day) and supratherapeutic doses (24 or 36 sprays/day) of THC/CBD spray on the QT/QTc interval in 258 healthy volunteers. The safety, tolerability, and pharmacokinetic profile of THC/CBD spray were also evaluated. Therapeutic and supratherapeutic doses of THC/CBD spray had no effect on cardiac repolarization with primary and secondary endpoints of QTcI and QTcF/QTcB, respectively, showing similar results. There was no indication of any effect on heart rate, atrioventricular conduction, or cardiac depolarization and no new clinically relevant morphological changes were observed. Overall, 19 subjects (25.0%) in the supratherapeutic (24/36 daily sprays of THC/CBD spray) dose group and one (1.6%) in the moxifloxacin group withdrew early due to intolerable AEs. Four psychiatric serious adverse events (AEs) in the highest dose group resulted in a reduction in the surpatherapeutic dose to 24 sprays/day. In conclusion, THC/CBD spray does not significantly affect ECG parameters. Additionally, THC/CBD spray is well tolerated at therapeutic doses with an AE profile similar to previous clinical studies. © The Author(s) 2013.

[Effect of pazufloxacin mesilate, a new quinolone antibacterial agent, for intravenous use on QT interval].

PubMed

Fukuda, Hitoshi; Morita, Yukie; Shiotani, Norio; Mizuo, Midori; Komae, Norihisa

2004-08-01

The potential for QT interval prolongation of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, was investigated by in vitro and in vivo electrophysiology studies. Following results were obtained. In vitro electrophysiology study using guinea pig papillary muscles: PZFX mesilate (30-300 microM) had no effects on resting membrane potential (RMP), action potential amplitude (APA) and action potential duration (APD). Reference quinolones, sparfloxacin (3-30 microM) and moxifloxacin (10-100 microM), had no effects on RMP and APA, but significantly prolonged APD at more than 3 and 10 microM, respectively, while ciprofloxacin (10-100 microM) had no effect on each parameter. In vivo electrophysiology study using anesthetized dogs: PZFX mesilate had no effects on electrocardiograph parameter (PR interval, QRS interval, QT interval and QTc) after intravenous administration of 3-30 mg/kg. These results suggest that PZFX mesilate has low potential for QT interval prolongation.

Impact of the Norepinephrine Prodrug Droxidopa on the QTc Interval in Healthy Individuals

PubMed Central

Hewitt, L. Arthur; Mehdirad, Ali A.

2017-01-01

Abstract A double‐blind, 4‐period crossover study (NCT01327066) was conducted to assess the effect of the novel norepinephrine prodrug droxidopa on the QT interval in in healthy subjects. Subjects were randomized to receive a single dose of droxidopa 600 mg (maximal dose) and 2000 mg (supratherapeutic dose) compared with the positive control, moxifloxacin 400 mg, and placebo, each separated by a 3‐day washout period. Patients were monitored by continuous Holter monitoring, and electrocardiograms (ECGs) were extracted 0.5–23 hours after dosing. Blood samples for pharmacokinetic analysis were collected before dosing and after ECG data collection. The primary end point was the time‐matched placebo‐adjusted change from baseline in the individually corrected QT (QTcI). The time‐averaged QTcI mean placebo‐corrected changes from baseline for droxidopa 600 and 2000 mg were 0.1 milliseconds (90%CI, ‐0.9 to 1.0 milliseconds) and 0.3 milliseconds (90%CI, ‐0.6 to 1.3 milliseconds), respectively, and 9 milliseconds (90%CI, 8.4–10.3 milliseconds) for moxifloxacin. This study found no effect of either dose of droxidopa on cardiac repolarization using QTcI. Analysis of the pharmacokinetic/pharmacodynamic relationship and cardiac repolarization showed no association with droxidopa exposure. There were no clinically relevant effects of droxidopa on heart rate, atrioventricular conduction, or cardiac depolarization identified. No morphologic ECG changes were observed. PMID:29024579

Predictive Analytics for Identification of Patients at Risk for QT Interval Prolongation - A Systematic Review.

PubMed

Tomaselli Muensterman, Elena; Tisdale, James E

2018-06-08

Prolongation of the heart rate-corrected QT (QTc) interval increases the risk for torsades de pointes (TdP), a potentially fatal arrhythmia. The likelihood of TdP is higher in patients with risk factors, which include female sex, older age, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, concomitant administration of ≥ 2 QTc interval-prolonging medications, among others. Assessment and quantification of risk factors may facilitate prediction of patients at highest risk for developing QTc interval prolongation and TdP. Investigators have utilized the field of predictive analytics, which generates predictions using techniques including data mining, modeling, machine learning, and others, to develop methods of risk quantification and prediction of QTc interval prolongation. Predictive analytics have also been incorporated into clinical decision support (CDS) tools to alert clinicians regarding patients at increased risk of developing QTc interval prolongation. The objectives of this paper are to assess the effectiveness of predictive analytics for identification of patients at risk of drug-induced QTc interval prolongation, and to discuss the efficacy of incorporation of predictive analytics into CDS tools in clinical practice. A systematic review of English language articles (human subjects only) was performed, yielding 57 articles, with an additional 4 articles identified from other sources; a total of 10 articles were included in this review. Risk scores for QTc interval prolongation have been developed in various patient populations including those in cardiac intensive care units (ICUs) and in broader populations of hospitalized or health system patients. One group developed a risk score that includes information regarding genetic polymorphisms; this score significantly predicted TdP. Development of QTc interval prolongation risk prediction models and incorporation of these models into CDS tools reduces the risk of QTc interval

Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure-response analysis.

PubMed

Freise, Kevin J; Dunbar, Martin; Jones, Aksana K; Hoffman, David; Enschede, Sari L Heitner; Wong, Shekman; Salem, Ahmed Hamed

2016-10-01

Venetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QTc) interval and to evaluate the relationship between systemic venetoclax concentration and QTc interval. The study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (n = 105) or non-Hodgkin's lymphoma (n = 71) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study. Electrocardiograms were collected in triplicate at time-matched points (2, 4, 6, and 8 h) prior to the first venetoclax administration and after repeated venetoclax administration to achieve steady state conditions. Venetoclax doses ranged from 100 to 1200 mg daily. Plasma venetoclax samples were collected after steady state electrocardiogram measurements. The mean and upper bound of the 2-sided 90 % confidence interval (CI) QTc change from baseline were <5 and <10 ms, respectively, at all time points and doses (<400, 400, and >400 mg). Three subjects had single QTc values >500 ms and/or ΔQTc > 60 ms. The effect of venetoclax concentration on both ΔQTc and QTc was not statistically significant (P > 0.05). At the mean maximum concentrations achieved with therapeutic (400 mg) and supra-therapeutic (1200 mg) venetoclax doses, the estimated drug effects on QTc were 0.137 (90 % CI [-1.01 to 1.28]) and 0.263 (90 % CI [-1.92 to 2.45]) ms, respectively. Venetoclax does not prolong QTc interval even at supra-therapeutic doses, and there is no relationship between venetoclax concentrations and QTc interval.

Identifying QT prolongation from ECG impressions using a general-purpose Natural Language Processor

PubMed Central

Denny, Joshua C.; Miller, Randolph A.; Waitman, Lemuel Russell; Arrieta, Mark; Peterson, Joshua F.

2009-01-01

Objective Typically detected via electrocardiograms (ECGs), QT interval prolongation is a known risk factor for sudden cardiac death. Since medications can promote or exacerbate the condition, detection of QT interval prolongation is important for clinical decision support. We investigated the accuracy of natural language processing (NLP) for identifying QT prolongation from cardiologist-generated, free-text ECG impressions compared to corrected QT (QTc) thresholds reported by ECG machines. Methods After integrating negation detection to a locally-developed natural language processor, the KnowledgeMap concept identifier, we evaluated NLP-based detection of QT prolongation compared to the calculated QTc on a set of 44,318 ECGs obtained from hospitalized patients. We also created a string query using regular expressions to identify QT prolongation. We calculated sensitivity and specificity of the methods using manual physician review of the cardiologist-generated reports as the gold standard. To investigate causes of “false positive” calculated QTc, we manually reviewed randomly selected ECGs with a long calculated QTc but no mention of QT prolongation. Separately, we validated the performance of the negation detection algorithm on 5,000 manually-categorized ECG phrases for any medical concept (not limited to QT prolongation) prior to developing the NLP query for QT prolongation. Results The NLP query for QT prolongation correctly identified 2,364 of 2,373 ECGs with QT prolongation with a sensitivity of 0.996 and a positive predictive value of 1.000. There were no false positives. The regular expression query had a sensitivity of 0.999 and positive predictive value of 0.982. In contrast, the positive predictive value of common QTc thresholds derived from ECG machines was 0.07–0.25 with corresponding sensitivities of 0.994–0.046. The negation detection algorithm had a recall of 0.973 and precision of 0.982 for 10,490 concepts found within ECG impressions

New in vitro model for proarrhythmia safety screening: IKs inhibition potentiates the QTc prolonging effect of IKr inhibitors in isolated guinea pig hearts.

PubMed

Kui, Péter; Orosz, Szabolcs; Takács, Hedvig; Sarusi, Annamária; Csík, Norbert; Rárosi, Ferenc; Csekő, Csongor; Varró, András; Papp, Julius Gy; Forster, Tamás; Farkas, Attila S; Farkas, András

2016-01-01

Preclinical in vivo QT measurement as a proarrhythmia essay is expensive and not reliable enough. The aim of the present study was to develop a sensitive, cost-effective, Langendorff perfused guinea pig heart model for proarrhythmia safety screening. Low concentrations of dofetilide and cisapride (inhibitors of the rapid delayed rectifier potassium current, IKr) were tested alone and co-perfused with HMR-1556 (inhibitor of the slow delayed rectifier potassium current, IKs) in Langendorff perfused guinea pig hearts. The electrocardiographic rate corrected QT (QTc) interval, the Tpeak-Tend interval and the beat-to-beat variability and instability (BVI) of the QT interval were determined in sinus rhythm. Dofetilide and HMR-1556 alone or co-perfused, prolonged the QTc interval by 20±2%, 10±1% and 55±10%, respectively. Similarly, cisapride and HMR-1556 alone or co-perfused, prolonged the QTc interval by 11±3%, 11±4% and 38±6%, respectively. Catecholamine-induced fast heart rate abolished the QTc prolonging effects of the IKr inhibitors, but augmented the QTc prolongation during IKs inhibition. None of the drug perfusions increased significantly the Tpeak-Tend interval and the sinus BVI of the QT interval. IKs inhibition increased the QTc prolonging effect of IKr inhibitors in a super-additive (synergistic) manner, and the QTc interval was superior to other proarrhythmia biomarkers measured in sinus rhythm in isolated guinea pig hearts. The effect of catecholamines on the QTc facilitated differentiation between IKr and IKs inhibitors. Thus, QTc measurement in Langendorff perfused guinea pig hearts with pharmacologically attenuated repolarization reserve and periodic catecholamine perfusion seems to be suitable for preclinical proarrhythmia screening. Copyright © 2016 Elsevier Inc. All rights reserved.

QT interval and dispersion in drug-free anorexia nervosa adolescents: a case control study.

PubMed

Bomba, Monica; Tremolizzo, Lucio; Corbetta, Fabiola; Nicosia, Franco; Lanfranconi, Francesca; Poggioli, Gianni; Goulene, Karine; Stramba-Badiale, Marco; Conti, Elisa; Neri, Francesca; Nacinovich, Renata

2017-11-16

Long QT values have been reported in patients with anorexia nervosa of the restricting type (ANr) potentially increasing the risk of fatal arrhythmia, especially if psychotropic drug treatment is required. Nevertheless, the previous studies on this topic are biased by drug exposure, long disease durations, and small sample sizes. This study is aimed at assessing QTc and QTcd values in ANr adolescents with recent onset and drug free, as compared to subjects affected by psychiatric disorders other than ANr. We evaluated QTc and its dispersion (QTcd) in a population of 77 drug-free ANr female adolescents and compared to an equal number of healthy controls (H-CTRL) and pathological controls (P-CTRL, mixed psychiatric disorders). The QT determination was performed on a standard simultaneous 12-lead ECG in blind by a single experienced investigator. QTc was calculated by the Bazett's formula and QTcd was determined as the difference between the maximum and minimum QTc intervals in different leads. Only for ANr patients, clinico-demographic data, hormones, and electrolytes were obtained. QTc was slightly reduced in ANr patients (27.7 ms, < 10%, p < 0.0003) vs. controls, while QTcd was increased in P-CTRL (30%, p < 0.0003). Heart rate was significantly lower in ANr patients vs. controls (25%; p < 0.003). Tyroid hormones and serum potassium showed weak although significant positive correlations with QTc in ANr patients. QTcd displayed a weak negative correlation with the BMI percentile (r = - 0.262, p = 0.03). We reject the hypothesis that QTc and QTcd are increased in drug-free ANr adolescents with a relatively short-disease duration. Further studies are needed to understand if the previously reported increase might be related to other associated chronic disorders, such as hormonal or electrolyte imbalance.

Prolonged corrected QT interval is predictive of future stroke events even in subjects without ECG-diagnosed left ventricular hypertrophy.

PubMed

Ishikawa, Joji; Ishikawa, Shizukiyo; Kario, Kazuomi

2015-03-01

We attempted to evaluate whether subjects who exhibit prolonged corrected QT (QTc) interval (≥440 ms in men and ≥460 ms in women) on ECG, with and without ECG-diagnosed left ventricular hypertrophy (ECG-LVH; Cornell product, ≥244 mV×ms), are at increased risk of stroke. Among the 10 643 subjects, there were a total of 375 stroke events during the follow-up period (128.7±28.1 months; 114 142 person-years). The subjects with prolonged QTc interval (hazard ratio, 2.13; 95% confidence interval, 1.22-3.73) had an increased risk of stroke even after adjustment for ECG-LVH (hazard ratio, 1.71; 95% confidence interval, 1.22-2.40). When we stratified the subjects into those with neither a prolonged QTc interval nor ECG-LVH, those with a prolonged QTc interval but without ECG-LVH, and those with ECG-LVH, multivariate-adjusted Cox proportional hazards analysis demonstrated that the subjects with prolonged QTc intervals but not ECG-LVH (1.2% of all subjects; incidence, 10.7%; hazard ratio, 2.70, 95% confidence interval, 1.48-4.94) and those with ECG-LVH (incidence, 7.9%; hazard ratio, 1.83; 95% confidence interval, 1.31-2.57) had an increased risk of stroke events, compared with those with neither a prolonged QTc interval nor ECG-LVH. In conclusion, prolonged QTc interval was associated with stroke risk even among patients without ECG-LVH in the general population. © 2014 American Heart Association, Inc.

QT correction formulas and laboratory analysis on patients with metabolic syndrome and diabetes

NASA Astrophysics Data System (ADS)

Wong, Sara; Rivera, Pedro; Rodríguez, María. G.; Severeyn, Érika; Altuve, Miguel

2013-11-01

This article presents a study of ventricular repolarization in diabetic and metabolic syndrome subjects. The corrected QT interval (QTc) was estimated using four correction formulas commonly employed in the literature: Bazett, Fridericia, Framingham and Hodges. After extracting the Q, R and T waves from the electrocardiogram of 52 subjects (19 diabetic, 15 with metabolic syndrome and 18 control), using a wavelet-based approach, the RR interval and QT interval were determined. Then, QTc interval was computed using the formulas previously mentioned. Additionally, laboratory test (fasting glucose, cholesterol, triglycerides) were also evaluated. Results show that metabolic syndrome subjects have normal QTc. However, a longer QTc in this population may be a sign of future complication. The corrected QT interval by Fridericia's formula seems to be the most appropriated for metabolic syndrome subjects (low correlation coefficient between RR and QTc). Significant differences were obtained in the blood glucose and triglyceride levels, principally due to the abnormal sugar metabolization of metabolic syndrome and diabetic subjects. Further studies are focused on the acquisition of a larger database of metabolic syndrome and diabetics subjects and the repetition of this study using other populations, like high performance athletes.

Impact of the Norepinephrine Prodrug Droxidopa on the QTc Interval in Healthy Individuals.

PubMed

White, William B; Hewitt, L Arthur; Mehdirad, Ali A

2018-03-01

A double-blind, 4-period crossover study (NCT01327066) was conducted to assess the effect of the novel norepinephrine prodrug droxidopa on the QT interval in in healthy subjects. Subjects were randomized to receive a single dose of droxidopa 600 mg (maximal dose) and 2000 mg (supratherapeutic dose) compared with the positive control, moxifloxacin 400 mg, and placebo, each separated by a 3-day washout period. Patients were monitored by continuous Holter monitoring, and electrocardiograms (ECGs) were extracted 0.5-23 hours after dosing. Blood samples for pharmacokinetic analysis were collected before dosing and after ECG data collection. The primary end point was the time-matched placebo-adjusted change from baseline in the individually corrected QT (QTcI). The time-averaged QTcI mean placebo-corrected changes from baseline for droxidopa 600 and 2000 mg were 0.1 milliseconds (90%CI, -0.9 to 1.0 milliseconds) and 0.3 milliseconds (90%CI, -0.6 to 1.3 milliseconds), respectively, and 9 milliseconds (90%CI, 8.4-10.3 milliseconds) for moxifloxacin. This study found no effect of either dose of droxidopa on cardiac repolarization using QTcI. Analysis of the pharmacokinetic/pharmacodynamic relationship and cardiac repolarization showed no association with droxidopa exposure. There were no clinically relevant effects of droxidopa on heart rate, atrioventricular conduction, or cardiac depolarization identified. No morphologic ECG changes were observed. © 2017 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

QT interval dispersion in the patients with central serous chorioretinopathy.

PubMed

Dagli, Necati; Turgut, Burak; Tanyildizi, Rumeysa; Kobat, Sabiha; Kobat, Mehmet Ali; Dogdu, Orhan

2015-01-01

To evaluate QT dispersion (QTD) in patients with central serous chorioretinopathy (CSC). This clinical, comperative, case-control study included 30 patients with CSC at acute phase (Group 1) and 30 age- and sex-matched healthy subjects (Group 2, the control group). From all subjects, a 12-lead surface electrocardiography was obtained. The heart rate (HR), QT maximum (QTmax), QT minimum (QTmin), QT corrected (QTc), QTD and Tmean were manually measured and analyzed. Student's t-test and Pearson's method of correlation were used for statistical analysis. The patient and control groups were matched for age, smoking status (rate and duration) and gender. There were no significant differences with regard to these among the groups (P>0.05). The participants included 19 men (63.3%) and 11 women (36.7%) in Group 1, 20 men (66.7%) and 10 women (33.3%) in Group 2. QTmax, QTD and QTc were significantly higher than those of healthy controls (P<0.001 for QTmax, P=0.01 for QTD and P=0.001 for QTc). QTmin, Tmean and HR did not differ significantly between the study groups (P=0.28 for QTmin, P=0.56 for Tmean and P>0.05 for HR). No significant correlation was found between duration of the disorder and QTD values (r=0.13, P>0.05). These findings suggest that CSC may be associated with an increase in QTD and that the patients might be at risk for ventricular arrhythmia.

[Association of cardiovascular autonomic neuropathy and prolonged QT interval with cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus].

PubMed

Ticse Aguirre, Ray; Villena, Jaime E

2011-03-01

In order to evaluate the relationship between cardiovascular autonomic neuropathy and corrected QT interval (QTc) with cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus, we followed up for 5 years 67 patients attending the outpatient Endocrinology Service. 82% completed follow-up and cardiovascular events occurred in 16 patients. We found that long QTc interval was the only variable significantly associated with cardiovascular morbidity and mortality in the multiple logistic regression analysis (RR: 13.56, 95% CI: 2.01-91.36) (p = 0.0074).

Evaluation of Tp-Te Interval and Tp-Te/QT Ratio in Patients with Coronary Slow Flow Tp-Te/QT Ratio and Coronary Slow Flow.

PubMed

Tenekecioglu, Erhan; Karaagac, Kemal; Yontar, Osman Can; Agca, Fahriye Vatansever; Ozluk, Ozlem Arican; Tutuncu, Ahmet; Arslan, Burhan; Yilmaz, Mustafa

2015-06-01

Coronary slow flow (CSF) phenomenon is described by angiographically normal coronary arteries with delayed opacification of the distal vasculature. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-Te) may correspond to the transmural dispersion of the repolarization and that increased Tp-Te interval and Tp-Te/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate the ventricular repolarization by using Tp-Te interval and Tp-Te/QT ratio in patients with CSF. This study included 50 CSF patients (40 male, mean age 48.6±12.5 years) and 40 control individuals (23 male, mean age 47.8±12.5 years). Tp-Te interval and Tp-Te/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared in groups. Baseline characteristics of the study groups were comparable. In electrocardiographic parameters analysis, QT and corrected QT were similar in CSF patients compared to the controls (357±35.2 vs 362±38.0 milliseconds and 419±25.8 vs 430±44.2 milliseconds, all p value >0.05). Tp-Te interval, Tp-Te/QT and Tp-Te/QTc ratio were significantly higher in CSF patients (85±13.7 vs 74±9.9 milliseconds and 0.24±0.03 vs 0.20±0.02 and 0.20±0.03 vs 0.17±0.02 all p value <0.001). Our study revealed that QTd, Tp-Te interval and Tp-Te/QT ratio are prolonged in patients with CSF.

Paced QT interval as a risk factor for new-onset left ventricular systolic dysfunction and cardiac death after permanent pacemaker implantation.

PubMed

Cho, Eun Jeong; Park, Seung-Jung; Park, Kyoung Min; On, Young Keun; Kim, June Soo

2016-01-15

Prolongation of corrected QT (QTc) interval reflects an increased risk of fatal arrhythmia and cardiac death in various populations. However, it is not clear whether the paced-QTc (p-QTc) interval is associated with new-onset left ventricular systolic dysfunction (new-LVSD) or cardiac death. In 491 consecutive patients (64 ± 14 years) with preserved LV ejection fraction (64 ± 7%), the p-QTc interval was measured within 2 weeks after PPM implantation. We assessed the rates of new-LVSD and cardiac death based on the degree of p-QTc interval. During the follow-up period (78 ± 51 months), new-LVSD and cardiac death were identified in 53 (10.8%) and 26 (5.3%) patients, respectively. Patients with new-LVSD had more frequent atrioventricular block (P=0.041), a higher percentage of ventricular pacing (P=0.005), a longer p-QRS duration (P<0.001), and more prolonged p-QTc interval (P<0.001) compared to those without new-LVSD. There was a graded increase in the rates of new-LVSD (P<0.001) and cardiac death (P=0.001) from the patients in the lowest to those in the highest tertile of the p-QTc interval. Additionally, the incidence of cardiac death was significantly elevated especially in the patients with new-LVSD and wider p-QTc interval. In Cox regression analyses, the p-QTc interval was independently associated with new-LVSD and cardiac death even after adjusted with various relevant confounding factors. Prolonged p-QTc interval was closely associated with new-LVSD and cardiac death after PPM implantation in patients with preserved LV systolic function. The rate of cardiac death significantly increased especially in patients who showed more p-QTc widening along with new-LVSD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A Valuable Tool in Predicting Poor Outcome due to Sepsis in Pediatric Intensive Care Unit: Tp-e/QT Ratio.

PubMed

Ozdemir, Rahmi; Isguder, Rana; Kucuk, Mehmet; Karadeniz, Cem; Ceylan, Gokhan; Katipoglu, Nagehan; Yilmazer, Murat Muhtar; Yozgat, Yilmaz; Mese, Timur; Agin, Hasan

2016-10-01

To assess the feasibility of 12-lead electrocardiographic (ECG) measures such as P wave dispersion (PWd), QT interval, QT dispersion (QTd), Tp-e interval, Tp-e/QT and Tp-e/QTc ratio in predicting poor outcome in patients diagnosed with sepsis in pediatric intensive care unit (PICU). Ninety-three patients diagnosed with sepsis, severe sepsis or septic shock and 103 age- and sex-matched healthy children were enrolled into the study. PWd, QT interval, QTd, Tp-e interval and Tp-e/QT, Tp-e/QTc ratios were obtained from a 12-lead electrocardiogram. PWd, QTd, Tp-e interval and Tp-e/QT, Tp-e/QTc ratios were significantly higher in septic patients compared with the controls. During the study period, 41 patients had died. In multivariate logistic regression analyses, only Tp-e/QT ratio was found to be an independent predictor of mortality. The ECG measurements can predict the poor outcome in patients with sepsis. The Tp-e/QT ratio may be a valuable tool in predicting mortality for patients with sepsis in the PICU. © The Author [2016]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

QT interval dispersion in the patients with central serous chorioretinopathy

PubMed Central

Dagli, Necati; Turgut, Burak; Tanyildizi, Rumeysa; Kobat, Sabiha; Kobat, Mehmet Ali; Dogdu, Orhan

2015-01-01

AIM To evaluate QT dispersion (QTD) in patients with central serous chorioretinopathy (CSC). METHODS This clinical, comperative, case-control study included 30 patients with CSC at acute phase (Group 1) and 30 age- and sex-matched healthy subjects (Group 2, the control group). From all subjects, a 12-lead surface electrocardiography was obtained. The heart rate (HR), QT maximum (QTmax), QT minimum (QTmin), QT corrected (QTc), QTD and Tmean were manually measured and analyzed. Student's t-test and Pearson's method of correlation were used for statistical analysis. RESULTS The patient and control groups were matched for age, smoking status (rate and duration) and gender. There were no significant differences with regard to these among the groups (P>0.05). The participants included 19 men (63.3%) and 11 women (36.7%) in Group 1, 20 men (66.7%) and 10 women (33.3%) in Group 2. QTmax, QTD and QTc were significantly higher than those of healthy controls (P<0.001 for QTmax, P=0.01 for QTD and P=0.001 for QTc). QTmin, Tmean and HR did not differ significantly between the study groups (P=0.28 for QTmin, P=0.56 for Tmean and P>0.05 for HR). No significant correlation was found between duration of the disorder and QTD values (r=0.13, P>0.05). CONCLUSION These findings suggest that CSC may be associated with an increase in QTD and that the patients might be at risk for ventricular arrhythmia. PMID:25709909

Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings.

PubMed

Noel, Gary J; Goodman, Daniel B; Chien, Shuchean; Solanki, Bhavna; Padmanabhan, Mukund; Natarajan, Jaya

2004-05-01

A clinical trial was conducted in healthy volunteers using both periodic and continuous ECG recordings to assess the effect of increasing doses of levofloxacin on the QT and QTc interval. Periodic and continuous ECGs were recorded before and after subjects were dosed with placebo and increasing doses of levofloxacin (500 mg, 1000 mg, 1500 mg) that included doses twice the maximum recommended dose of 750 mg in a double-blind, randomized, four-period, four-sequence crossover trial. Mean heart rate (HR) and the QT and QTc interval after dosing with levofloxacin and placebo were compared, and HR-QT interval relationships defined by linear regression analysis were calculated. After single doses of 1000 and 1500 mg of levofloxacin, HR increased significantly, as measured by periodic and continuous ECG recordings. This transient increase occurred at times of peak plasma concentration and was without symptoms. Mean QT intervals after placebo and mean intervals after levofloxacin were indistinguishable. Using periodic ECG recordings, single doses of 1500 mg were associated with small increases in QTc that were statistically significant. In contrast, an effect on QTc was shown only using the Bazett formula with data obtained from continuous ECG recordings. Together with the finding that levofloxacin does not influence HR-QT relationships, these findings suggest that levofloxacin has little effect on prolonging ventricular repolarization and that small increases in HR associated with high doses of levofloxacin contribute to the drug's apparent effect on QTc. Single doses of 1000 or 1500 mg of levofloxacin transiently increase HR without affecting the uncorrected QT interval. Differences in mean QTc after levofloxacin compared to placebo vary depending on the correction formula used and whether the data analyzed are from periodic or continuous ECG recordings. This work suggests that using continuous ECG recordings in assessing QT/QTc effects of drugs may be of value

Olanzapine induced Q-Tc shortening.

PubMed

Shoja Shafti, Saeed; Fallah Jahromi, Parisa

2014-12-01

Prolongation of Q-Tc interval is commonly accepted as a surrogate marker for the ability of a drug to cause torsade de pointes. In the present study, safety of olanzapine versus risperidone was compared among a group of patients with schizophrenia to see the frequency of the electrocardiographic alterations induced by those atypical antipsychotics. Two hundred and sixty-eight female inpatients with schizophrenia entered in one of the two parallel groups to participate in an open study for random assignment to olanzapine (n = 148) or risperidone (n = 120). Standard 12-lead surface electrocardiogram (ECG) was taken from each patient at baseline, before initiation of treatment, and then at the end of management, just before discharge. The parameters that were assessed included heart rate (HR), P-R interval, QRS interval, Q-T interval (corrected = Q-Tc), ventricular activation time (VAT), ST segment, T wave, axis of QRS, and finally, interventricular conduction process. A total of 37.83% of cases in the olanzapine group and 30% in the risperidone group showed some Q-Tc changes; 13.51% and 24.32% of the patients in the olanzapine group showed prolongation and shortening of the Q-Tc, respectively, while changes in the risperidone group were restricted to only prolongation of Q-Tc. Comparison of means showed a significant increment in Q-Tc by risperidone (p = 0.02). Also, comparison of proportions in the olanzapine group showed significantly more cases with shortening of Q-Tc versus its prolongation (p = 0.01). No significant alterations with respect to other variables were evident. Olanzapine and risperidone had comparable potentiality for induction of Q-Tc changes, while production of further miscellaneous alterations in ECG was more observable in the olanzapine group compared with the risperidone group. Also shortening of Q-Tc was specific to olanzapine.

Interleukin-1β gene variants are associated with QTc interval prolongation following cardiac surgery: a prospective observational study.

PubMed

Kertai, Miklos D; Ji, Yunqi; Li, Yi-Ju; Mathew, Joseph P; Daubert, James P; Podgoreanu, Mihai V

2016-04-01

We characterized cardiac surgery-induced dynamic changes of the corrected QT (QTc) interval and tested the hypothesis that genetic factors are associated with perioperative QTc prolongation independent of clinical and procedural factors. All study subjects were ascertained from a prospective study of patients who underwent elective cardiac surgery during August 1999 to April 2002. We defined a prolonged QTc interval as > 440 msec, measured from 24-hr pre- and postoperative 12-lead electrocardiograms. The association of 37 single nucleotide polymorphisms (SNPs) in 21 candidate genes -involved in modulating arrhythmia susceptibility pathways with postoperative QTc changes- was investigated in a two-stage design with a stage I cohort (n = 497) nested within a stage II cohort (n = 957). Empirical P values (Pemp) were obtained by permutation tests with 10,000 repeats. After adjusting for clinical and procedural risk factors, we selected four SNPs (P value range, 0.03-0.1) in stage I, which we then tested in the stage II cohort. Two functional SNPs in the pro-inflammatory cytokine interleukin-1β (IL1β), rs1143633 (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.53 to 0.95; Pemp = 0.02) and rs16944 (OR, 1.31; 95% CI, 1.01 to 1.70; Pemp = 0.04), remained independent predictors of postoperative QTc prolongation. The ability of a clinico-genetic model incorporating the two IL1B polymorphisms to classify patients at risk for developing prolonged postoperative QTc was superior to a clinical model alone, with a net reclassification improvement of 0.308 (P = 0.0003) and an integrated discrimination improvement of 0.02 (P = 0.000024). The results suggest a contribution of IL1β in modulating susceptibility to postoperative QTc prolongation after cardiac surgery.

Interleukin-1β gene variants are associated with QTc interval prolongation following cardiac surgery: a prospective observational study

PubMed Central

Kertai, Miklos D.; Ji, Yunqi; Li, Yi-Ju; Mathew, Joseph P.; Daubert, James P.; Podgoreanu, Mihai V.

2016-01-01

Background We characterized cardiac surgery-induced dynamic changes of the corrected QT (QTc) interval and tested the hypothesis that genetic factors are associated with perioperative QTc prolongation independent of clinical and procedural factors. Methods All study subjects were ascertained from a prospective study of patients who underwent elective cardiac surgery during August 1999 to April 2002. We defined a prolonged QTc interval as >440 msec, measured from 24-hr pre- and postoperative 12-lead electrocardiograms. The association of 37 single nucleotide polymorphisms (SNPs) in 21 candidate genes – involved in modulating arrhythmia susceptibility pathways with postoperative QTc changes–was investigated in a two-stage design with a stage I cohort (n = 497) nested within a stage II cohort (n = 957). Empirical P values (Pemp) were obtained by permutation tests with 10,000 repeats. Results After adjusting for clinical and procedural risk factors, we selected four SNPs (P value range, 0.03-0.1) in stage I, which we then tested in the stage II cohort. Two functional SNPs in the pro-inflammatory cytokine interleukin-1β (IL1β), rs1143633 (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.53 to 0.95; Pemp = 0.02) and rs16944 (OR, 1.31; 95% CI, 1.01 to 1.70; Pemp = 0.04), remained independent predictors of postoperative QTc prolongation. The ability of a clinico-genetic model incorporating the two IL1B polymorphisms to classify patients at risk for developing prolonged postoperative QTc was superior to a clinical model alone, with a net reclassification improvement of 0.308 (P = 0.0003) and an integrated discrimination improvement of 0.02 (P = 0.000024). Conclusion The results suggest a contribution of IL1β in modulating susceptibility to postoperative QTc prolongation after cardiac surgery. PMID:26858093

Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers

PubMed Central

Loghin, Corina; Haber, Harry; Beasley, Charles M; Kothare, Prajakti A; Kauffman, Lynnette; April, John; Jin, Ling; Allen, Albert J; Mitchell, Malcolm I

2013-01-01

Aim The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared. Methods Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time-matched baseline on days −2 and −1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo-subtracted change from baseline model-corrected QT (QTcM) on day 7 was the primary endpoint. Results QTcM differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one-sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one-sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QTc was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QTcM for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration−QTc change observed was consistent with the literature. Conclusion Atomoxetine was not associated with a clinically significant change in QTc. However, a statistically significant increase in QTc was associated with increasing plasma concentrations. PMID:22803597

Increased risk of QT prolongation associated with atherosclerotic diseases in arseniasis-endemic area in southwestern coast of Taiwan

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, C.-H.; Chen, C.-L.; Hsiao, C.K.

2009-09-15

Chronic arsenic exposure has been documented to be associated with various cardiovascular diseases. We aimed to investigate 1) the increased risk of QT prolongation in chronic arsenic exposure, and 2) the relationships of cardiac repolarization (QT interval duration) with ischemic heart disease and carotid atherosclerosis. We studied 280 men and 355 women living in the endemic area of arseniasis in southwestern Taiwan. QT intervals in electrocardiogram and carotid intima-media thickness (IMT) by ultrasonography were measured. Ischemic heart disease was diagnosed by history or abnormal electrocardiogram. Significant associations of the corrected QT interval (QTc) duration with ischemic heart disease and carotidmore » intima-medium thickness and plaque were observed after adjustment for various risk factors in the multiple linear regression analysis (all p values < 0.05). Three indices of chronic arsenic exposure were all significantly associated with the risk of QTc prolongation showing dose-response relationships (p < 0.001). Chronic arsenic exposure was dose-dependently associated with the risk of QTc prolongation. Ischemic heart disease and carotid atherosclerosis were significantly associated with QTc intervals in chronic arsenic exposure. QTc prolongation might be suggested as an early biomarker for ischemic heart disease or carotid atherosclerosis in population with previous exposure to arsenic.« less

Single therapeutic and supratherapeutic doses of corifollitropin alfa, a sustained follicle stimulant, do not prolong the QTcF-interval in healthy postmenopausal volunteers.

PubMed

de Kam, Pieter-Jan; van Kuijk, Jacqueline H M; Zandvliet, Anthe S; Thomsen, Torben

2015-09-01

Corifollitropin alfa (Elonva®) is the first hybrid follicle-stimulating hormone molecule with demonstrated sustained follicle-stimulating activity after a single subcutaneous injection. This trial evaluated if corifollitropin alfa is associated with QT/QTc prolongation and/ or proarrhythmic potential as compared to placebo in healthy post-menopausal women. Participants were healthy, postmenopausal women. Study treatments were corifollitropin alfa 150 μg, corifollitropin alfa 240 μg, and moxifloxacin 400 mg with placebo. This randomized, double blind, double-dummy, 4-period crossover trial compared single doses of corifollitropin alfa 150 μg (therapeutic dose), corifollitropin alfa 240 μg (supratherapeutic dose), and moxifloxacin 400 mg (positive control) with placebo. Corifollitropin alfa was administered on day 1 and moxifloxacin on day 2. The largest time-matched mean QTcF difference versus placebo for the therapeutic dose of corifollitropin alfa was 1.4 ms (upper limit of 1-sided 95% confidence interval (UL 95% CI) = 3.4 ms), and for the supratherapeutic dose was 1.2 ms (UL 95% CI = 3.6 ms). For both the therapeutic and the supratherapeutic dose of corifollitropin alfa and at all time points, the UL 95% CI for the time matched QTcF differences compared with placebo was below 10 ms, the threshold of relevance defined by the ICH E14 guideline. Single therapeutic and supratherapeutic doses of corifollitropin alfa are not associated with clinically relevant QT/QTc-interval prolongation in healthy post-menopausal women.

Strategies to reduce the risk of drug-induced QT interval prolongation: a pharmaceutical company perspective.

PubMed

Pollard, C E; Valentin, J-P; Hammond, T G

2008-08-01

Drug-induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the 'Thorough QT/QTc Study' -- as defined in the clinical regulatory guidance (ICH E14) -- are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least an in vivo QT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG and in vivo non-clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high-benefit drugs for serious indications may never be marketed.

Comparison of the effects of various airway devices on hemodynamic response and QTc interval in rabbits under general anesthesia.

PubMed

Toman, Huseyin; Erbas, Mesut; Sahin, Hasan; Kiraz, Hasan Ali; Uzun, Metehan; Ovali, Mehmet Akif

2015-12-01

In this study, we aimed to compare the effects of various airway devices on QTc interval in rabbits under general anesthesia. The subjects were randomly separated into four groups: Group ETT, Group LMA, Group PLA, Group V-gel. Baseline values and hearth rate, mean arterial pressure and ECG was obtained at the 1st, 5th and 30th minutes after administration of anesthesia and placement of airway device and, QTc interval was evaluated. Difference was observed between ET group and V-gel group in the 5th minute mean arterial pressure values (p < 0.05). It was observed that QTc intervals at the 1st and 5th minute in the ET group significantly increased when compared with the other groups (p < 0.05). Again, it was observed that QTc interval of ET group at the 15th and 30th minute was longer when compared with PLA and V-gel groups (p < 0.05). It was also observed that QTc interval of LMA Group at the 5th minute after intubation significantly increased when compared with V-gel group (p < 0.05). It was observed that HR values of ETT group at the 1st, 5th and 15th minutes after intubation increased with regards to PLA and V-gel groups (p < 0.05). It was determined that the 30th minute hearth rate of ETT group was higher when compared to V-gel group (p < 0.05). In our study we observed that V-gel Rabbit affected both hemodynamic response and QT interval less than other airway devices.

Prolongation of heart rate-corrected QT interval is a predictor of cardiac autonomic dysfunction in patients with systemic lupus erythematosus.

PubMed

Nomura, Atsushi; Kishimoto, Mitsumasa; Takahashi, Osamu; Deshpande, Gautam A; Yamaguchi, Kenichi; Okada, Masato

2014-05-01

Heart rate-corrected QT interval duration (QTc) has been shown to be related to cardiac autonomic dysfunction in patients with diabetes mellitus, although this association has not been previously described in patients with systemic lupus erythematosus (SLE). We retrospectively reviewed the medical records of 91 SLE patients and 144 non-SLE connective tissue disease patients visiting our clinic from November 2010 to April 2011. We compared ambulatory heart rate identified by pulse measured by automated machine in an outpatient waiting area versus resting heart rate identified on prior screening electrocardiogram. Heart rate differences were analyzed in relation to QTc interval and other characteristics. Ambulatory and resting heart rate differences were larger among SLE patients with QTc prolongation (QTc > 430 ms) than those without QTc prolongation (mean difference, 15.9 vs. 9.6, p = 0.001). In multivariate analysis, differences in heart rate were associated with QTc prolongation (OR 1.10, 95 % CI 1.01-1.21; p = 0.038), independent of age, duration of disease, immunosuppressant use, hydroxychloroquine use, diabetes mellitus, cardiac abnormality, anti-Ro/SS-A antibody positivity, or resting heart rate. Cardiac autonomic dysfunction is a common manifestation of SLE and may be related to QTc prolongation.

Short-Duration Spaceflight Does Not Prolong QTc Intervals in Male Astronauts

NASA Technical Reports Server (NTRS)

Mitchell, Brett M.; Meck, Janice V.

2004-01-01

Although ventricular dysrhythmias are not increased during, and QTc intervals are not prolonged after, short-duration (5 to 16 days) spaceflights, QTc intervals have not previously been reported during these shorter flights. Holter monitor recordings, obtained in 11 male astronauts who flew on shuttle missions ranging from 5 to 10 days, showed that QTc intervals did not change significantly 10 days before launch, on 2 separate days of spaceflight, and 2 days after landing. Taken together, these data and our previous report show that QTc interval prolongation occurs sometime between the 9th and 30th days of spaceflight.

Effect of mood states on QT interval and QT dispersion in eating disorder patients.

PubMed

Takimoto, Yoshiyuki; Yoshiuchi, Kazuhiro; Akabayashi, Akira

2008-04-01

Prolonged QT interval and QT dispersion have been reported in patients with eating disorders. Although the factors that cause prolongation remain unclear, mood states such as anxiety have been reported to influence QT interval and dispersion, probably via the autonomic nervous system. Therefore the aim of the present paper was to investigate mood effect on prolonged QT interval and QT dispersion. The subjects were 47 female anorexia nervosa (AN) and 48 female bulimia nervosa (BN) patients. In all of the patients, serum electrolyte levels were normal. QT interval and QT dispersion were measured from 12-lead electrocardiographic recordings. Mood states in each patient were measured using a Profile of Mood States (POMS) evaluation, and the patients were divided into high- and low-score groups for each POMS subscale. The differences in QT variables were compared between the two groups for each subscale. In the BN group, QT interval and QT dispersion in the high depression score group were significantly longer than those in the low depression score group, and QT dispersion was significantly greater in the high anxiety score group than in the low anxiety score group. In addition, QT interval and QT dispersion were significantly correlated with depression scores. In the AN group there were no significant differences in QT interval or QT dispersion between the high- and low-score groups for any POMS subscale. BN patients with worse states of depression or anxiety had longer QT intervals and larger QT dispersion. In BN patients, mood disturbance might increase the risk of arrhythmias.

Differential Changes in QTc Duration during In-Hospital Haloperidol Use

PubMed Central

Blom, Marieke T.; Bardai, Abdennasser; van Munster, Barbara C.; Nieuwland, Mei-Ing; de Jong, Hendrik; van Hoeijen, Daniel A.; Spanjaart, Anne M.; de Boer, Anthonius; de Rooij, Sophia E.; Tan, Hanno L.

2011-01-01

Aims To evaluate changes in QT duration during low-dose haloperidol use, and determine associations between clinical variables and potentially dangerous QT prolongation. Methods In a retrospective cohort study in a tertiary university teaching hospital in The Netherlands, all 1788 patients receiving haloperidol between 2005 and 2007 were studied; ninety-seven were suitable for final analysis. Rate-corrected QT duration (QTc) was measured before, during and after haloperidol use. Clinical variables before haloperidol use and at the time of each ECG recording were retrieved from hospital charts. Mixed model analysis was used to estimate changes in QT duration. Risk factors for potentially dangerous QT prolongation were estimated by logistic regression analysis. Results Patients with normal before-haloperidol QTc duration (male ≤430 ms, female ≤450 ms) had a significant increase in QTc duration of 23 ms during haloperidol use; twenty-three percent of patients rose to abnormal levels (male ≥450 ms, female ≥470 ms). In contrast, a significant decrease occurred in patients with borderline (male 430–450 ms, female 450–470 ms) or abnormal before-haloperidol QTc duration (15 ms and 46 ms, respectively); twenty-three percent of patients in the borderline group, and only 9% of patients in the abnormal group obtained abnormal levels. Potentially dangerous QTc prolongation was independently associated with surgery before haloperidol use (ORadj 34.9, p = 0.009) and before-haloperidol QTc duration (ORadj 0.94, p = 0.004). Conclusion QTc duration during haloperidol use changes differentially, increasing in patients with normal before-haloperidol QTc duration, but decreasing in patients with prolonged before-haloperidol QTc duration. Shorter before-haloperidol QTc duration and surgery before haloperidol use predict potentially dangerous QTc prolongation. PMID:21961030

Effects of anthracycline, cyclophosphamide and taxane chemotherapy on QTc measurements in patients with breast cancer.

PubMed

Veronese, Pedro; Hachul, Denise Tessariol; Scanavacca, Mauricio Ibrahim; Hajjar, Ludhmila Abrahão; Wu, Tan Chen; Sacilotto, Luciana; Veronese, Carolina; Darrieux, Francisco Carlos da Costa

2018-01-01

Acute and subacute cardiotoxicity are characterized by prolongation of the corrected QT interval (QTc) and other measures derived from the QTc interval, such as QTc dispersion (QTdc) and transmural dispersion of repolarization (DTpTe). Although anthracyclines prolong the QTc interval, it is unclear whether breast cancer patients who undergo the ACT chemotherapy regimen of anthracycline (doxorubicin: A), cyclophosphamide (C) and taxane (T) may present with QTc, QTdc and DTpTe prolongation. Twenty-three consecutive patients with breast cancer were followed prospectively during ACT chemotherapy and were analyzed according to their QT measurements. QTc, QTdc and DTpTe measurements were determined by a 12-lead electrocardiogram (EKG) prior to chemotherapy (baseline), immediately after the first phase of anthracycline and cyclophosphamide (AC) treatment, and immediately after T treatment. Serum troponin and B-type natriuretic peptide (BNP) levels were also measured. Compared to baseline values, the QTc interval was significantly prolonged after the AC phase (439.7 ± 33.2 ms vs. 472.5 ± 36.3 ms, p = 0.001) and after T treatment (439.7 ± 33.2 ms vs. 467.9 ± 42.6 ms, p < 0.001). Troponin levels were elevated after the AC phase (23.0 pg/mL [min-max: 6.0-85.0] vs. 6.0 pg/mL [min-max: 6.0-22.0], p < 0.001) and after T treatment (25.0 pg/mL [min-max: 6.0-80.0] vs. 6.0 pg/mL [min-max: 6.0-22.0], p < 0.001) compared to baseline values. In this prospective study of patients with non-metastatic breast cancer who underwent ACT chemotherapy, significant QTc prolongation and an elevation in serum troponin levels were observed.

Sex Hormones and the QT Interval: A Review

PubMed Central

Sedlak, Tara; Shufelt, Chrisandra; Iribarren, Carlos

2012-01-01

Abstract A prolonged QT interval is a marker for an increased risk of ventricular tachyarrhythmias. Both endogenous and exogenous sex hormones have been shown to affect the QT interval. Endogenous testosterone and progesterone shorten the action potential, and estrogen lengthens the QT interval. During a single menstrual cycle, progesterone levels, but not estrogen levels, have the dominant effect on ventricular repolarization in women. Studies of menopausal hormone therapy (MHT) in the form of estrogen-alone therapy (ET) and estrogen plus progesterone therapy (EPT) have suggested a counterbalancing effect of exogenous estrogen and progesterone on the QT. Specifically, ET lengthens the QT, whereas EPT has no effect. To date, there are no studies on oral contraception (OC) and the QT interval, and future research is needed. This review outlines the current literature on sex hormones and QT interval, including the endogenous effects of estrogen, progesterone, and testosterone and the exogenous effects of estrogen and progesterone therapy in the forms of MHT and hormone contraception. Further, we review the potential mechanisms and pathophysiology of sex hormones on the QT interval. PMID:22663191

Prevalence, Risk Factors and In-hospital Outcomes of QTc Interval Prolongation in Liver Cirrhosis.

PubMed

Zhao, Jiancheng; Qi, Xingshun; Hou, Feifei; Ning, Zheng; Zhang, Xintong; Deng, Han; Peng, Ying; Li, Jing; Wang, Xiaoxi; Li, Hongyu; Guo, Xiaozhong

2016-09-01

QTc interval prolongation is an electrocardiographic abnormality in liver cirrhosis. The objective of this study was to evaluate the prevalence, risk factors and in-hospital outcomes of QTc interval prolongation in Chinese patients with liver cirrhosis. This was a retrospective analysis of a total of 1,268 patients with liver cirrhosis who were consecutively admitted to our hospital between January 2011 and June 2014. QTc interval data were collected from the medical records. QTc interval prolongation was defined as QTc interval > 440 milliseconds. The prevalence of QTc interval prolongation was 38.2% (485 of 1268). In the entire cohort, the risk factors for QTc interval prolongation included an older age, a higher proportion of alcohol abuse and ascites, higher bilirubin, blood urea nitrogen, creatinine, prothrombin time, international normalized ratio, Child-Pugh score and model for end-stage liver diseases score, and lower red blood cell (RBC), hemoglobin (Hb), albumin (ALB), alanine aminotransferase and calcium. The in-hospital mortality was not significantly different between patients with and without QTc interval prolongation (2.1% versus 1.3%, P = 0.276). In the subgroup analyses of patients with hepatitis B virus or alcohol alone-related liver cirrhosis, the risk factors included higher bilirubin, creatinine, prothrombin time, international normalized ratio, Child-Pugh score and model for end-stage liver diseases score, and lower RBC, Hb and ALB. In the subgroups analyses of patients with acute upper gastrointestinal bleeding or ascites, the risk factors included lower RBC, Hb and ALB. QTc interval prolongation was frequent in liver cirrhosis. Although QTc interval prolongation was positively associated with alcohol-related liver cirrhosis and more severe liver dysfunction, it did not significantly influence the in-hospital mortality. Copyright © 2016 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

The prognostic value of the QT interval and QT interval dispersion in all-cause and cardiac mortality and morbidity in a population of Danish citizens.

PubMed

Elming, H; Holm, E; Jun, L; Torp-Pedersen, C; Køber, L; Kircshoff, M; Malik, M; Camm, J

1998-09-01

To evaluate the prognostic value of the QT interval and QT interval dispersion in total and in cardiovascular mortality, as well as in cardiac morbidity, in a general population. The QT interval was measured in all leads from a standard 12-lead ECG in a random sample of 1658 women and 1797 men aged 30-60 years. QT interval dispersion was calculated from the maximal difference between QT intervals in any two leads. All cause mortality over 13 years, and cardiovascular mortality as well as cardiac morbidity over 11 years, were the main outcome parameters. Subjects with a prolonged QT interval (430 ms or more) or prolonged QT interval dispersion (80 ms or more) were at higher risk of cardiovascular death and cardiac morbidity than subjects whose QT interval was less than 360 ms, or whose QT interval dispersion was less than 30 ms. Cardiovascular death relative risk ratios, adjusted for age, gender, myocardial infarct, angina pectoris, diabetes mellitus, arterial hypertension, smoking habits, serum cholesterol level, and heart rate were 2.9 for the QT interval (95% confidence interval 1.1-7.8) and 4.4 for QT interval dispersion (95% confidence interval 1.0-19-1). Fatal and non-fatal cardiac morbidity relative risk ratios were similar, at 2.7 (95% confidence interval 1.4-5.5) for the QT interval and 2.2 (95% confidence interval 1.1-4.0) for QT interval dispersion. Prolongation of the QT interval and QT interval dispersion independently affected the prognosis of cardiovascular mortality and cardiac fatal and non-fatal morbidity in a general population over 11 years.

Analyzing Thorough QT Study 1 & 2 in the Telemetric and Holter ECG Warehouse (THEW) using Hannover ECG System HES : A validation study.

PubMed

Khawaja, A; Petrovic, R; Safer, A; Baas, T; Dössel, O; Fischer, R

2010-01-01

Following the ICH E14 clinical evaluation guideline [1], the measurement of QT/QTc interval prolongation has become the standard surrogate biomarker for cardiac drug safety assessment and the faith of a drug development. In Thorough QT (TQT) study, a so-called positive control is employed to assess the ability of this study to detect the endpoint of interest, i.e. the QT prolongation by about five milliseconds. In other words the lower bound of the one-sided 95% confidence interval (CI) must be above 0 [ms]. Fully automated detection of ECG fiducial points and measurement of the corresponding intervals including QT intervals and RR intervals vary between different computerized algorithms. In this work we demonstrate the ability and reliability of Hannover ECG System (HES(®)) to assess drug effects by detecting QT/QTc prolongation effects that meet the threshold of regulatory concern as mentioned by using THEW database studies namely TQT studies one and two.

New age- and sex-specific criteria for QT prolongation based on rate correction formulas that minimize bias at the upper normal limits.

PubMed

Rautaharju, Pentti M; Mason, Jay W; Akiyama, Toshio

2014-07-01

Existing formulas for rate-corrected QT (QTc) commonly fail to properly adjust the upper normal limits which are more critical than the mean QTc for evaluation of prolonged QT. Age- and sex-related differences in QTc are also often overlooked. Our goal was to establish criteria for prolonged QTc using formulas that minimize QTc bias at the upper normal limits. Strict criteria were used in selecting a study group of 57,595 persons aged 5 to 89 years (54% women) and to exclude electrocardiograms (ECG) with possible disease-associated changes. Two QT rate adjustment formulas were identified which both minimized rate-dependency in the 98 th percentile limits: QTcmod, based on an electrophysiological model (QTcMod = QTx(120 + HR)/180)), and QTcLogLin, a power function of the RR interval with exponents 0.37 for men and 0.38 for women. QTc shortened in men during adolescence and QTcMod became 13 ms shorter than in women at age 20-29 years. The sex difference was maintained through adulthood although decreasing with age. The criteria established for prolonged QTc were: Age < 40 years, men 430 ms, women 440 ms; Age 40 to 69, men 440 ms, women 450 ms; Age ≥ 70 years, men 455 ms, and women 460 ms. Sex difference in QTc originates from shortened QT in adolescent males. Upper normal limits for QTc vary substantially by age and sex, and it is essential to use age- and sex-specific criteria for evaluation of QT prolongation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Magnitude of increase in QTc interval after initiation of dofetilide in patients with persistent atrial fibrillation is associated with increased rates of pharmacological cardioversion and long-term freedom from recurrent atrial fibrillation.

PubMed

Huang, Henry D; Waks, Jonathan W; Steinhaus, Daniel A; Zimetbaum, Peter

2016-07-01

Dofetilide is a class III antiarrhythmic drug approved for the treatment of atrial fibrillation (AF). Dofetilide-induced corrected QT (QTc) interval prolongation is a surrogate for the degree of drug effect, but the relationships between drug-induced QTc interval prolongation, pharmacological cardioversion (PCV), and freedom from recurrent AF are unclear. The purpose of this study was to assess associations between QTc interval change during dofetilide initiation and PCV and long-term AF recurrence. We performed retrospective analyses of a prospective cohort of patients with AF admitted for dofetilide initiation between 2001 and 2014. Clinical characteristics and electrocardiographic variables were assessed. We evaluated outcomes of successful PCV in patients with persistent AF and time to recurrence of AF in patients with paroxysmal and persistent AF. During the study, 243 patients with persistent AF and 176 patients with paroxysmal AF initiated dofetilide. PCV occurred in 93/243 (41.7%) patients with persistent AF. After multivariable adjustment, QTc interval change was associated with PCV (adjusted odds ratio 1.21; P = .003 per 10-ms QTc increase). Inhospital QTc interval change was associated with long-term freedom from AF in patients with persistent AF (adjusted hazard ratio 0.92; P = .011 at 4 years per 10-ms QTc increase), but not in patients with paroxysmal AF. In patients with persistent AF, PCV was also associated with long-term freedom from recurrent AF (adjusted hazard ratio 0.62; P = .009 at 4 years). The magnitude of QTc interval prolongation during dofetilide initiation is an independent predictor of successful PCV and long-term freedom from arrhythmia in patients with persistent AF. QTc interval change had no association with AF recurrence in patients with paroxysmal AF, suggesting that different mechanisms of arrhythmogenesis may be operant in different AF types. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

The association of long-term glycaemic variability versus sustained chronic hyperglycaemia with heart rate-corrected QT interval in patients with type 2 diabetes.

PubMed

Su, Jian-Bin; Yang, Xiao-Hua; Zhang, Xiu-Lin; Cai, Hong-Li; Huang, Hai-Yan; Zhao, Li-Hua; Xu, Feng; Chen, Tong; Cheng, Xing-Bo; Wang, Xue-Qin; Lu, Yan

2017-01-01

Prolonged heart rate-corrected QT(QTc) interval is related to ventricular arrhythmia and cardiovascular mortality, with considerably high prevalence of type 2 diabetes. Additionally, long-term glycaemic variability could be a significant risk factor for diabetic complications in addition to chronic hyperglycaemia. We compared the associations of long-term glycaemic variability versus sustained chronic hyperglycaemia with the QTc interval among type 2 diabetes patients. In this cross-sectional study, 2904 type 2 diabetes patients were recruited who had undergone at least four fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (PPG) measurements (at least once for every 3 months, respectively) during the preceding year. Long-term glycaemic variabilities of FPG and 2-hour PPG were assessed by their standard deviations (SD-FPG and SD-PPG, respectively), and chronic fasting and postprandial hyperglycaemia were assessed by their means (M-FPG and M-PPG, respectively). HbA1c was also determined upon enrolment to assess current overall glycaemic control. QTc interval was estimated from resting 12-lead electrocardiograms, and more than 440 ms was considered abnormally prolonged. Patients with prolonged QTc interval (≥440 ms) had greater M-FPG, M-PPG, SD-PPG and HbA1c than those with normal QTc interval but comparable SD-FPG. QTc interval was correlated with M-FPG, M-PPG, SD-PPG and HbA1c (r = 0.133, 0.153, 0.245 and 0.207, respectively, p = 0.000) but not with SD-FPG (r = 0.024, p = 0.189). After adjusting for metabolic risk factors via multiple linear regression analysis, SD-PPG, M-PPG and HbA1c (t = 12.16, 2.69 and 10.16, respectively, p = 0.000) were the major independent contributors to the increased QTc interval. The proportion of prolonged QTc interval increased significantly from 10.9% to 14.2% to 26.6% for the first (T1) to second (T2) to third (T3) tertiles of SD-PPG. After adjusting via multiple logistic regression analysis, the odd ratios of

Value of the "Standing Test" in the Diagnosis and Evaluation of Beta-blocker Therapy Response in Long QT Syndrome.

PubMed

Muñoz-Esparza, Carmen; Zorio, Esther; Domingo Valero, Diana; Peñafiel-Verdú, Pablo; Sánchez-Muñoz, Juan J; García-Molina, Esperanza; Sabater, María; Navarro, Marina; San-Román, Irene; Pérez, Inmaculada; Santos, Juan J; Cabañas-Perianes, Valentín; Valdés, Mariano; Pascual, Domingo; García-Alberola, Arcadio; Gimeno Blanes, Juan R

2017-11-01

Patients with congenital long QT syndrome (LQTS) have an abnormal QT adaptation to sudden changes in heart rate provoked by standing. The present study sought to evaluate the standing test in a cohort of LQTS patients and to assess if this QT maladaptation phenomenon is ameliorated by beta-blocker therapy. Electrographic assessments were performed at baseline and immediately after standing in 36 LQTS patients (6 LQT1 [17%], 20 LQT2 [56%], 3 LQT7 [8%], 7 unidentified-genotype patients [19%]) and 41 controls. The corrected QT interval (QTc) was measured at baseline (QTc supine ) and immediately after standing (QTc standing ); the QTc change from baseline (ΔQTc) was calculated as QTc standing - QTc supine . The test was repeated in 26 patients receiving beta-blocker therapy. Both QTc standing and ΔQTc were significantly higher in the LQTS group than in controls (QTc standing , 528 ± 46ms vs 420 ± 15ms, P < .0001; ΔQTc, 78 ± 40ms vs 8 ± 13ms, P < .0001). No significant differences were noted between LQT1 and LQT2 patients. Typical ST-T wave patterns appeared after standing in LQTS patients. Receiver operating characteristic curves of QTc standing and ΔQTc showed a significant increase in diagnostic value compared with the QTc supine (area under the curve for both, 0.99 vs 0.85; P < .001). Beta-blockers attenuated the response to standing in LQTS patients (QTc standing , 440 ± 32ms, P < .0001; ΔQTc, 14 ± 16ms, P < .0001). Evaluation of the QTc after the simple maneuver of standing shows a high diagnostic performance and could be important for monitoring the effects of beta-blocker therapy in LQTS patients. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Prolongation of the QTc interval in African children treated for falciparum malaria.

PubMed

vn Seidlein, L; Jaffar, S; Greenwood, B

1997-05-01

Antimalarial drugs can affect the heart and trigger life-threatening arrhythmias. However, little is known about the frequency with which cardiac abnormalities occur during uncomplicated attacks of malaria. Therefore, we have studied the electrocardiograms of 139 Gambian children with uncomplicated falciparum malaria who were treated with co-artemether, pyrimethamine/sulfadoxine, or chloriquine. The QTc intervals were measured on presentation, and four and eight days after treatment. No significant differences in mean QTc or heart rate were found between children in the three treatment groups on days 0, 4, or 8. After adjustment for the type of antimalarial thearapy in an analysis of variance, the mean (SD) QTc intervals on days 0, 4, and 8 were 402 (22.6), 416 (23.1), and 405 (24.3) msec, respectively. The mean QTc on day 4 was significantly longer than the mean QTc on days 0 or 8 (P < 0.01 in both cases). A quadratic line was fitted for QTc against time for each antimalarial therapy. No significant differences were found between the quadratic lines of the three groups. A weak association was found between QTc and the degree of parasitemia (r = 0.17, P = 0.04) and temperature (r = -0.23, P = 0.01) measured on day 0. The QTcs were measured in 18 children who experienced a second episode of malaria. The changes in QTc observed during second episodes were similar to those observed during the first attack. Changes in QTc in five children who developed severe malaria were similar to those found in the remaining children who did not develop severe malaria. This study indicates that the QTc interval changes during the early phase of malaria and this change is independent of the type of antimalarial therapy given.

Obstructive Sleep Apnea in Patients with Congenital Long QT Syndrome: Implications for Increased Risk of Sudden Cardiac Death.

PubMed

Shamsuzzaman, Abu S; Somers, Virend K; Knilans, Timothy K; Ackerman, Michael J; Wang, Yu; Amin, Raouf S

2015-07-01

Congenital long QT syndrome (LQTS) is a familial arrhythmogenic cardiac channelopathy characterized by prolonged ventricular repolarization and increased risk of torsades de pointes-mediated syncope, seizures, and sudden cardiac death (SCD). QT prolongation corrected for heart rate (QTc) is an important diagnostic and prognostic feature in LQTS. Obstructive sleep apnea (OSA) has been increasingly implicated in the pathogenesis of cardiovascular disease, including arrhythmias and SCD. We tested the hypothesis that the presence of concomitant OSA in patients with LQTS is associated with increased QT intervals, both during sleep and while awake. Polysomnography with simultaneous overnight 12-lead electrocardiography (ECG) was recorded in 54 patients with congenital LQTS and 67 control subjects. OSA was diagnosed as apnea-hypopnea index (AHI) ≥ 5 events/h for adults and AHI > 1 event/h for children. RR and QT intervals were measured from the 12-lead surface ECG. QTc was determined by the Bazett formula. Respiratory disturbance index, AHI, and arousal index were significantly increased in patients with LQTS and with OSA compared to those without OSA and control subjects. QTc during different sleep stages and while awake was also significantly increased in patients with LQTS and OSA compared to those without OSA. Severity of OSA in patients with LQTS was directly associated with the degree of QTc. The presence and severity of obstructive sleep apnea (OSA) in patients with congenital long QT syndrome (LQTS) is associated with increased QT prolongation corrected for heart rate, which is an important biomarker of sudden cardiac death (SCD). Treatment of OSA in LQTS patients may reduce QT prolongation, thus reducing the risk of LQT-triggered SCD. © 2015 Associated Professional Sleep Societies, LLC.

QT effect of semagacestat at therapeutic and supratherapeutic doses.

PubMed

Zhang, Wei; Ayan-Oshodi, Mosun; Willis, Brian A; Annes, William; Hall, Stephen D; Chiesa, Joseph; Seger, Mary

2012-04-01

This thorough QT/ QT interval corrected for heart rate (QTc) study was designed to assess the potential of semagacestat, a functional gamma-secretase inhibitor, to delay cardiac repolarization. In this Phase I, single-dose, randomized, 4-period crossover study, semagacestat was compared with placebo in 54 healthy male and female subjects between the ages of 19 and 63 years, inclusive. Each study period included single oral-dose administrations of semagacestat 140 mg, semagacestat 280 mg, moxifloxacin 400 mg, or placebo. Study subjects and the investigator were blinded to the identity of semagacestat and placebo; however, moxifloxacin was administered as open-label. Moxifloxacin was compared with placebo for assay sensitivity analysis. Pharmacokinetic parameters were also assessed. For each QTc, the upper bound of the 2-sided 90% confidence interval (CI) for the least squares mean difference between semagacestat (at both the 140- and 280-mg dose levels) and placebo was < 10 msec at all time points, and thus, within the limits set for clinical relevance in regulatory guidelines. The results of this study indicate that single doses of 140 and 280 mg semagacestat did not prolong QTc to a clinically significant degree.

Association of functional genetic variants of A-kinase anchoring protein 10 with QT interval length in full-term Polish newborns.

PubMed

Łoniewska, Beata; Kaczmarczyk, Mariusz; Clark, Jeremy Simon; Gorący, Iwona; Horodnicka-Józwa, Anita; Ciechanowicz, Andrzej

2015-03-16

A-Kinase Anchoring Proteins (AKAPs) coordinate the specificity of protein kinase A signaling by localizing the kinase to subcellular sites. The 1936G (V646) AKAP10 allele has been associated in adults with low cholinergic/vagus nerve sensitivity, shortened PR intervals in ECG recording and in newborns with increased blood pressure and higher cholesterol cord blood concentration. The aim of the study was to answer the question of whether 1936A > G AKAP10 polymorphism is associated with the newborn electrocardiographic variables. Electrocardiograms were recorded from 114 consecutive healthy Polish newborns (55 females, 59 males), born after 37 gestational weeks to healthy women with uncomplicated pregnancies. All recordings were made between 3(rd) and 7(th) day of life to avoid QT variability. The heart rate per minute and duration of PR, QRS, RR and QT intervals were usually measured. The ECGs were evaluated independently by three observers. At birth, cord blood of neonates was obtained for isolation of genomic DNA. The distribution of anthropometric and electrocardiographic variables in our cohort approached normality (skewness < 2 for all variables). No significant differences in anthropometric variables and electrocardiographic traits with respect to AKAP10 genotype were found. Multiple regression analysis with adjustment for gender, gestational age and birth mass revealed that QTc interval in GG AKAP10 homozygotes was significantly longer, but in range, when compared with A alleles carriers (AA + AG, recessive mode of inheritance). No rhythm disturbances were observed. Results demonstrate possible association between AKAP10 1936A > G variant and QTc interval in Polish newborns.

Lack of significant effect of bilastine administered at therapeutic and supratherapeutic doses and concomitantly with ketoconazole on ventricular repolarization: results of a thorough QT study (TQTS) with QT-concentration analysis.

PubMed

Tyl, Benoît; Kabbaj, Meriam; Azzam, Sara; Sologuren, Ander; Valiente, Román; Reinbolt, Elizabeth; Roupe, Kathryn; Blanco, Nathalie; Wheeler, William

2012-06-01

The effect of bilastine on cardiac repolarization was studied in 30 healthy participants during a multiple-dose, triple-dummy, crossover, thorough QT study that included 5 arms: placebo, active control (400 mg moxifloxacin), bilastine at therapeutic and supratherapeutic doses (20 mg and 100 mg once daily, respectively), and bilastine 20 mg administered with ketoconazole 400 mg. Time-matched, triplicate electrocardiograms (ECGs) were recorded with 13 time points extracted predose and 16 extracted over 72 hours post day 4 dosing. Four QT/RR corrections were implemented: QTcB; QTcF; a linear individual correction (QTcNi), the primary correction; and a nonlinear one (QTcNnl). Moxifloxacin was associated with a significant increase in QTcNi at all time points between 1 and 12 hours, inclusively. Bilastine administration at 20 mg and 100 mg had no clinically significant impact on QTc (maximum increase in QTcNi, 5.02 ms; upper confidence limit [UCL] of the 1-sided, 95% confidence interval, 7.87 ms). Concomitant administration of ketoconazole and bilastine 20 mg induced a clinically relevant increase in QTc (maximum increase in QTcNi, 9.3 ms; UCL, 12.16 ms). This result was most likely related to the cardiac effect of ketoconazole because for all time points, bilastine plasma concentrations were lower than those observed following the supratherapeutic dose.

Underestimated and unreported prolonged QTc by automated ECG analysis in patients on methadone: can we rely on computer reading?

PubMed

Talebi, Soheila; Azhir, Alaleh; Zuber, Sam; Soman, Sandeep; Visco, Ferdinand; Totouom-Tangho, Holly; Kalantar, Hossein; Worku Hassen, Getaw

2015-04-01

Recognition of prolonged corrected QT (QTc) interval is of particular importance, especially when using medications known to prolong QTc interval. Methadone can prolong the QTc interval and has the potential to induce torsades de pointes. The objective of this study is to investigate the accuracy of computerized ECG analysis in correctly identifying and reporting QTc interval in patients on methadone. We conducted a retrospective review of ECGs in the Muse electronic database of patients on methadone who are above 18 years old between January 2012 and December 2013 at an urban community hospital. ECGs were analyzed by the Marquette 12SL ECG Analysis Program (GE'Healthcare) reviewed by a cardiologist. A total of 826 ECGs of patients on methadone were examined manually for the QTc interval, of which 625 (75.7%) had QTc less than 470 ms, 149 (18%) had QTc between 470-499 ms and 52 (6.3%) had QTc more than 499 ms. QTc between 470-499 ms was underestimated by machine in 19 (12.8%) ECGs and QTc more than 499 ms was underestimated in 10 (19.6%) when compared to manually calculated QTc. QTc prolongation was underreported in 63 ECGs (48.5%) of those whose QTc between 470-499 ms and in 1 ECG (2.4%) of those whose QTc was more than 499 ms. QTc can be underestimated or unreported by the computer analysis. Physicians not only should calculate QTc manually but also examine the actual QTc value displayed on the report before concluding that this parameter is normal, especially in patients who are at risk of QTc prolongation.

Testosterone-mediated upregulation of delayed rectifier potassium channel in cardiomyocytes causes abbreviation of QT intervals in rats.

PubMed

Masuda, Kimiko; Takanari, Hiroki; Morishima, Masaki; Ma, FangFang; Wang, Yan; Takahashi, Naohiko; Ono, Katsushige

2018-01-13

Men have shorter rate-corrected QT intervals (QTc) than women, especially at the period of adolescence or later. The aim of this study was to elucidate the long-term effects of testosterone on cardiac excitability parameters including electrocardiogram (ECG) and potassium channel current. Testosterone shortened QT intervals in ECG in castrated male rats, not immediately after, but on day 2 or later. Expression of Kv7.1 (KCNQ1) mRNA was significantly upregulated by testosterone in cardiomyocytes of male and female rats. Short-term application of testosterone was without effect on delayed rectifier potassium channel current (I Ks ), whereas I Ks was significantly increased in cardiomyocytes treated with dihydrotestosterone for 24 h, which was mimicked by isoproterenol (24 h). Gene-selective inhibitors of a transcription factor SP1, mithramycin, abolished the effects of testosterone on Kv7.1. Testosterone increases Kv7.1-I Ks possibly through a pathway related to a transcription factor SP1, suggesting a genomic effect of testosterone as an active factor for cardiac excitability.

Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women.

PubMed

Stier, Brendt; Fossler, Michael; Liu, Feng; Caltabiano, Stephen

2015-07-01

Retosiban is a small molecule oxytocin receptor antagonist that is under evaluation in clinical studies for treatment of spontaneous preterm labor. A Thorough QT/QTc study was conducted to evaluate the effect of retosiban on cardiac repolarization according to International Conference on Harmonization E14 guidance. This was a randomized, placebo- and positive-controlled, single-dose, crossover study of healthy men and women. All study participants received a 100 mg dose of retosiban (therapeutic target exposure), a 800 mg dose of retosiban (supratherapeutic target exposure), a 400 mg dose of moxifloxacin (positive control), and placebo with an appropriate washout. Holter monitoring data at baseline (predose) and at 13 subsequent time points during the next 24 hours were extracted and manually read by a central ECG reader who was blinded to the treatment assignment and corrected for heart rate by using the Fridericia formula (QTcF). A linear exposure-QTc response model was developed: ΔΔQTcF=RI+Cp,R⋅RS+MI+Cp,M⋅MS, where RI and MI are intercept terms for retosiban and moxifloxacin, respectively, RS and MS are slope terms for retosiban and moxifloxacin, respectively, and Cp,R and Cp,M are plasma concentrations for retosiban and moxifloxacin, respectively. A total of 52 healthy men (n = 27) and women (n = 25), with a mean age of 32 years, were enrolled in the study, and 43 (83%) completed all treatment periods and assessments. Mean placebo-corrected change from baseline QT (ΔΔQTcF) for the 2 retosiban dose groups revealed statistically significant decreases in ΔΔQTcF between 2 and 3 hours after administration, reaching a value of -2.5 msec for both retosiban dose groups. The 400 mg moxifloxacin group had a statistically significant increase in the ΔΔQTcF value at 0.75 hours after administration, reaching a maximal increase of 11.10 msec at 4 hours after administration. Results of the exposure-QTc response modeling revealed that there was no significant

A Thorough QT Study To Evaluate the Effects of Therapeutic and Supratherapeutic Doses of Delafloxacin on Cardiac Repolarization

PubMed Central

Benedict, Michael S.; Thorn, Michael D.; Lawrence, Laura E.; Cammarata, Sue K.; Sun, Eugene

2015-01-01

A randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug. PMID:25845864

Drug-physiology interaction and its influence on the QT prolongation-mechanistic modeling study.

PubMed

Wiśniowska, Barbara; Polak, Sebastian

2018-06-01

The current study is an example of drug-disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology-ten Tusscher ventricular cardiomyocyte cell model-was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies. Simulated and observed mean QTc values with standard deviation (SD) for each reported study point were compared and differences were analyzed with Student's t test (α = 0.05). The simulated results reflected the QTc interval changes measured in patients, as well as their clinically observed interindividual variability. The QTc interval changes were highly correlated with the change in plasma potassium both in clinical studies and in the simulations (Pearson's correlation coefficient > 0.55). The results suggest that the modeling and simulation approach could provide valuable quantitative insight into the cardiological effect of the potassium and heart rate changes caused by electrophysiologically inactive, non-cardiological drugs. This allows to simulate and predict the joint effect of several risk factors for QT prolongation, e.g., drug-dependent QT prolongation due to the ion channels inhibition and the current patient physiological conditions.

The QT Interval and Risk of Incident Atrial Fibrillation

PubMed Central

Mandyam, Mala C.; Soliman, Elsayed Z.; Alonso, Alvaro; Dewland, Thomas A.; Heckbert, Susan R.; Vittinghoff, Eric; Cummings, Steven R.; Ellinor, Patrick T.; Chaitman, Bernard R.; Stocke, Karen; Applegate, William B.; Arking, Dan E.; Butler, Javed; Loehr, Laura R.; Magnani, Jared W.; Murphy, Rachel A.; Satterfield, Suzanne; Newman, Anne B.; Marcus, Gregory M.

2013-01-01

BACKGROUND Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine. OBJECTIVE To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF. METHODS We examined a prolonged QT corrected by the Framingham formula (QTFram) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (Health ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by other formulae. RESULTS Among 14,538 ARIC participants, a prolonged QTFram predicted a roughly two-fold increased risk of AF (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.42–2.96, p<0.001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in CHS and Health ABC and were similar across various QT correction methods. Also in ARIC, each 10-ms increase in QTFram was associated with an increased unadjusted (HR 1.14, 95%CI 1.10–1.17, p<0.001) and adjusted (HR 1.11, 95%CI 1.07–1.14, p<0.001) risk of AF. Findings regarding a short QT were inconsistent across cohorts. CONCLUSIONS A prolonged QT interval is associated with an increased risk of incident AF. PMID:23872693

Associations between Changes in City and Address Specific Temperature and QT Interval - The VA Normative Aging Study

PubMed Central

Mehta, Amar J.; Kloog, Itai; Zanobetti, Antonella; Coull, Brent A.; Sparrow, David; Vokonas, Pantel; Schwartz, Joel

2014-01-01

Background The underlying mechanisms of the association between ambient temperature and cardiovascular morbidity and mortality are not well understood, particularly for daily temperature variability. We evaluated if daily mean temperature and standard deviation of temperature was associated with heart rate-corrected QT interval (QTc) duration, a marker of ventricular repolarization in a prospective cohort of older men. Methods This longitudinal analysis included 487 older men participating in the VA Normative Aging Study with up to three visits between 2000–2008 (n = 743). We analyzed associations between QTc and moving averages (1–7, 14, 21, and 28 days) of the 24-hour mean and standard deviation of temperature as measured from a local weather monitor, and the 24-hour mean temperature estimated from a spatiotemporal prediction model, in time-varying linear mixed-effect regression. Effect modification by season, diabetes, coronary heart disease, obesity, and age was also evaluated. Results Higher mean temperature as measured from the local monitor, and estimated from the prediction model, was associated with longer QTc at moving averages of 21 and 28 days. Increased 24-hr standard deviation of temperature was associated with longer QTc at moving averages from 4 and up to 28 days; a 1.9°C interquartile range increase in 4-day moving average standard deviation of temperature was associated with a 2.8 msec (95%CI: 0.4, 5.2) longer QTc. Associations between 24-hr standard deviation of temperature and QTc were stronger in colder months, and in participants with diabetes and coronary heart disease. Conclusion/Significance In this sample of older men, elevated mean temperature was associated with longer QTc, and increased variability of temperature was associated with longer QTc, particularly during colder months and among individuals with diabetes and coronary heart disease. These findings may offer insight of an important underlying mechanism of temperature

A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization.

PubMed

Litwin, Jeffrey S; Benedict, Michael S; Thorn, Michael D; Lawrence, Laura E; Cammarata, Sue K; Sun, Eugene

2015-01-01

A randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Prevalence and Outcome of High-Risk QT Prolongation Recorded in the Emergency Department from an Institution-Wide QT Alert System.

PubMed

Anderson, Heather N; Bos, J Martijn; Haugaa, Kristina H; Morlan, Bruce W; Tarrell, Robert F; Caraballo, Pedro J; Ackerman, Michael J

2018-01-01

QT prolongation is an independent risk factor for sudden death, stroke, and all-cause mortality. However, additional studies have shown that in certain settings, QT prolongation may be transient and a result of external factors. In this study, we evaluated the clinical characteristics and outcomes of patients seen in the emergency department (ED) with QT prolongation. Between November 2010 and June 2011, 7522 patients had an electrocardiogram (ECG) obtained during their evaluation in the ED. Clinical, laboratory, and therapeutic information was collected for all patients with QT prolongation (i.e., ≥ 500 ms and QRS < 120 ms). Potential QT-inciting factors (drugs, electrolyte disturbances, and comorbidities) were synthesized into a pro-QT score. Among the 7522 patients with an ECG obtained in the ED, a QT alert was activated in 93 (1.2%; mean QTc 521 ± 34 ms). The majority of ED patients (64%) had more than one underlying condition associated with QT prolongation, with electrolyte disturbances in 51%, a QT prolonging condition in 56%, and QT-prolonging drugs in 77%. Thirty-day mortality was 13% for patients with QT prolongation noted in the ED. One percent of patients evaluated with an ECG in the ED activated our prolonged QTc warning system, with most demonstrating > 1 QT-prolonging condition. Thirty-day mortality was significant, but it requires further investigation to determine whether the QTc simply provided a non-invasive indicator of increased risk or heralded the presence of a vulnerable host at risk of a QT-mediated sudden dysrhythmic death. Copyright © 2017 Elsevier Inc. All rights reserved.

Hyperglycemia and subsequent torsades de pointes with marked QT prolongation during refeeding.

PubMed

Nakashima, Takashi; Kubota, Tomoki; Takasugi, Nobuhiro; Kitagawa, Yuichiro; Yoshida, Takahiro; Ushikoshi, Hiroaki; Kawasaki, Masanori; Nishigaki, Kazuhiko; Ogura, Shinji; Minatoguchi, Shinya

2017-01-01

A fatal cardiac complication can occasionally present in malnourished patients during refeeding; this is known as refeeding syndrome. However, to our knowledge, hyperglycemia preceding torsades de pointes with QT prolongation during refeeding has not been reported. In the present study, we present a case in which hyperglycemia preceded torsades de pointes with QT prolongation during refeeding. The aim of this study was to determine the possible mechanism underlying QT prolongation during refeeding and indicate how to prevent it. A 32-y-old severely malnourished woman (body mass index 14.57 kg/m 2 ) was admitted to the intensive care unit of our institution after resuscitation from cardiopulmonary arrest due to ventricular fibrillation. She was diagnosed with anorexia nervosa. Although no obvious electrolyte abnormalities were observed, her blood glucose level was 11 mg/dL. A 12-lead electrocardiogram at admission showed sinus rhythm with normal QT interval (QTc 0.448). Forty mL of 50% glucose (containing 20 g of glucose) was intravenously injected, followed by a drip infusion of glucose to maintain blood glucose level within normal range. After 9 h, the patient's blood glucose level increased to 569 mg/dL. However, after 38 h, an episode of marked QT prolongation (QTc 0.931) followed by torsades de pointes developed. Hyperglycemia during refeeding can present with QT prolongation; consequently, monitoring blood glucose levels may be useful in avoiding hyperglycemia, which can result in QT prolongation. Furthermore, additional monitoring of QT intervals using a 12-lead electrocardiogram should allow the early detection of QT prolongation when glucose solution is administered to a malnourished patient with (severe) hypoglycemia. Copyright © 2016 Elsevier Inc. All rights reserved.

[The effect of esmolol on corrected-QT interval, corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients taking an angiotensin-converting enzyme inhibitor].

PubMed

Ceker, Zahit; Takmaz, Suna Akın; Baltaci, Bülent; Başar, Hülya

2015-01-01

The importance of minimizing the exaggerated sympatho-adrenergic responses and QT interval and QT interval dispersion changes that may develop due to laryngoscopy and tracheal intubation during anesthesia induction in the hypertensive patients is clear. Esmolol decreases the hemodynamic response to laryngoscopy and intubation. However, the effect of esmolol in decreasing the prolonged QT interval and QT interval dispersion as induced by laryngoscopy and intubation is controversial. We investigated the effect of esmolol on the hemodynamic, and corrected-QT interval and corrected-QT interval dispersion changes seen during anesthesia induction in hypertensive patients using angiotensin converting enzyme inhibitors. 60 ASA I-II patients, with essential hypertension using angiotensin converting enzyme inhibitors were included in the study. The esmolol group received esmolol at a bolus dose of 500mcg/kg followed by a 100mcg/kg/min infusion which continued until the 4th min after intubation. The control group received 0.9% saline similar to the esmolol group. The mean blood pressure, heart rate values and the electrocardiogram records were obtained as baseline values before the anesthesia, 5min after esmolol and saline administration, 3min after the induction and 30s, 2min and 4min after intubation. The corrected-QT interval was shorter in the esmolol group (p=0.012), the corrected-QT interval dispersion interval was longer in the control group (p=0.034) and the mean heart rate was higher in the control group (p=0.022) 30s after intubation. The risk of arrhythmia frequency was higher in the control group in the 4-min period following intubation (p=0.038). Endotracheal intubation was found to prolong corrected-QT interval and corrected-QT interval dispersion, and increase the heart rate during anesthesia induction with propofol in hypertensive patients using angiotensin converting enzyme inhibitors. These effects were prevented with esmolol (500mcg/kg bolus, followed by

Can non‐clinical repolarization assays predict the results of clinical thorough QT studies? Results from a research consortium

PubMed Central

Park, Eunjung; Gintant, Gary A; Bi, Daoqin; Kozeli, Devi; Pettit, Syril D; Skinner, Matthew; Willard, James; Wisialowski, Todd; Koerner, John; Valentin, Jean‐Pierre

2018-01-01

Background and Purpose Translation of non‐clinical markers of delayed ventricular repolarization to clinical prolongation of the QT interval corrected for heart rate (QTc) (a biomarker for torsades de pointes proarrhythmia) remains an issue in drug discovery and regulatory evaluations. We retrospectively analysed 150 drug applications in a US Food and Drug Administration database to determine the utility of established non‐clinical in vitro IKr current human ether‐à‐go‐go‐related gene (hERG), action potential duration (APD) and in vivo (QTc) repolarization assays to detect and predict clinical QTc prolongation. Experimental Approach The predictive performance of three non‐clinical assays was compared with clinical thorough QT study outcomes based on free clinical plasma drug concentrations using sensitivity and specificity, receiver operating characteristic (ROC) curves, positive (PPVs) and negative predictive values (NPVs) and likelihood ratios (LRs). Key Results Non‐clinical assays demonstrated robust specificity (high true negative rate) but poor sensitivity (low true positive rate) for clinical QTc prolongation at low‐intermediate (1×–30×) clinical exposure multiples. The QTc assay provided the most robust PPVs and NPVs (ability to predict clinical QTc prolongation). ROC curves (overall test accuracy) and LRs (ability to influence post‐test probabilities) demonstrated overall marginal performance for hERG and QTc assays (best at 30× exposures), while the APD assay demonstrated minimal value. Conclusions and Implications The predictive value of hERG, APD and QTc assays varies, with drug concentrations strongly affecting translational performance. While useful in guiding preclinical candidates without clinical QT prolongation, hERG and QTc repolarization assays provide greater value compared with the APD assay. PMID:29181850

Effects of conventional vs high-dose rocuronium on the QTc interval during anesthesia induction and intubation in patients undergoing coronary artery surgery: a randomized, double-blind, parallel trial

PubMed Central

Öztürk, T.; Ağdanlı, D.; Bayturan, Ö.; Çıkrıkcı, C.; Keleş, G.T.

2015-01-01

Myocardial ischemia, as well as the induction agents used in anesthesia, may cause corrected QT interval (QTc) prolongation. The objective of this randomized, double-blind trial was to determine the effects of high- vs conventional-dose bolus rocuronium on QTc duration and the incidence of dysrhythmias following anesthesia induction and intubation. Fifty patients about to undergo coronary artery surgery were randomly allocated to receive conventional-dose (0.6 mg/kg, group C, n=25) or high-dose (1.2 mg/kg, group H, n=25) rocuronium after induction with etomidate and fentanyl. QTc, heart rate, and mean arterial pressure were recorded before induction (T0), after induction (T1), after rocuronium (just before laryngoscopy; T2), 2 min after intubation (T3), and 5 min after intubation (T4). The occurrence of dysrhythmias was recorded. In both groups, QTc was significantly longer at T3 than at baseline [475 vs 429 ms in group C (P=0.001), and 459 vs 434 ms in group H (P=0.005)]. The incidence of dysrhythmias in group C (28%) and in group H (24%) was similar. The QTc after high-dose rocuronium was not significantly longer than after conventional-dose rocuronium in patients about to undergo coronary artery surgery who were induced with etomidate and fentanyl. In both groups, compared with baseline, QTc was most prolonged at 2 min after intubation, suggesting that QTc prolongation may be due to the nociceptive stimulus of intubation. PMID:25714880

Tp-e Interval, Tp-e/QTc Ratio, and Fragmented QRS Are Correlated with the Severity of Liver Cirrhosis.

PubMed

Akboga, Mehmet Kadri; Yuksel, Mahmut; Balci, Kevser Gulcihan; Kaplan, Mustafa; Cay, Serkan; Gokbulut, Volkan; Yayla, Cagri; Ertem, Ahmet Goktug; Ayhan, Meral Akdogan; Topaloglu, Serkan; Aras, Dursun

2017-01-01

Arrhythmias and electrocardiographic changes are reported in several noncardiac diseases, including liver cirrhosis (LC). We intended to evaluate the interval from the peak to the end of the electrocardiographic T wave (Tp-e), Tp-e/QTc ratio, and fQRS as presumed markers of arrhythmias in LC. In this cross-sectional study, a total of 88 consecutive patients with LC according to clinical, biological, ultrasonographic, or histological criteria and 73 control subjects were enrolled. The severity of cirrhosis was classified according to Pugh-Child's classification and Model for End-Stage Liver Disease (MELD) score. Tp-e interval, Tp-e/QTc ratio, and fQRS rates were measured from the 12-lead electrocardiogram. Tp-e interval, Tp-e/QTc ratio and fQRS rates were significantly increased in parallel to the severity of LC (P < 0.001, P < 0.001, and P = 0.003, respectively). In correlation analysis, Pugh-Child stage showed a significantly positive correlation with Tp-e interval (r = 0.462, P < 0.001), QTc interval (r = 0.373, P < 0.001), Tp-e/QTc ratio (r = 0.352, P < 0.001), and fQRS (r = 0.407, P < 0.001). Furthermore, Tp-e interval (r = 0.414, P < 0.001) and Tp-e/QTc ratio (r = 0.426, P< 0.001) had significant positive correlation with MELD score. Our study demonstrated that Tp-e interval, Tp-e/QTc ratios, and fQRS rates were significantly increased in parallel to the severity of LC. Thus, these findings may implicate that Tp-e interval, Tp-e/QTc ratio, and fQRS may be novel and useful indicators for prediction of arrhythmias in LC. © 2016 Wiley Periodicals, Inc.

Tafenoquine at therapeutic concentrations does not prolong fridericia-corrected QT interval in healthy subjects

PubMed Central

Green, Justin A; Patel, Apurva K; Patel, Bela R; Hussaini, Azra; Harrell, Emma J; McDonald, Mirna J; Carter, Nick; Mohamed, Khadeeja; Duparc, Stephan; Miller, Ann K

2014-01-01

Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18–65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine–QTcF concentration–effect relationship demonstrated a shallow slope (0.5 ms/μg mL–1) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization. PMID:24700490

Tafenoquine at therapeutic concentrations does not prolong Fridericia-corrected QT interval in healthy subjects.

PubMed

Green, Justin A; Patel, Apurva K; Patel, Bela R; Hussaini, Azra; Harrell, Emma J; McDonald, Mirna J; Carter, Nick; Mohamed, Khadeeja; Duparc, Stephan; Miller, Ann K

2014-09-01

Tafenoquine is being developed for relapse prevention in Plasmodium vivax malaria. This Phase I, single-blind, randomized, placebo- and active-controlled parallel group study investigated whether tafenoquine at supratherapeutic and therapeutic concentrations prolonged cardiac repolarization in healthy volunteers. Subjects aged 18-65 years were randomized to one of five treatment groups (n = 52 per group) to receive placebo, tafenoquine 300, 600, or 1200 mg, or moxifloxacin 400 mg (positive control). Lack of effect was demonstrated if the upper 90% CI of the change from baseline in QTcF following supratherapeutic tafenoquine 1200 mg versus placebo (ΔΔQTcF) was <10 milliseconds for all pre-defined time points. The maximum ΔΔQTcF with tafenoquine 1200 mg (n = 50) was 6.39 milliseconds (90% CI 2.85, 9.94) at 72 hours post-final dose; that is, lack of effect for prolongation of cardiac depolarization was demonstrated. Tafenoquine 300 mg (n = 48) or 600 mg (n = 52) had no effect on ΔΔQTcF. Pharmacokinetic/pharmacodynamic modeling of the tafenoquine-QTcF concentration-effect relationship demonstrated a shallow slope (0.5 ms/μg mL(-1) ) over a wide concentration range. For moxifloxacin (n = 51), maximum ΔΔQTcF was 8.52 milliseconds (90% CI 5.00, 12.04), demonstrating assay sensitivity. In this thorough QT/QTc study, tafenoquine did not have a clinically meaningful effect on cardiac repolarization. © 2014, The American College of Clinical Pharmacology.

Common Genetic Variant Risk Score Is Associated With Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

PubMed

Strauss, David G; Vicente, Jose; Johannesen, Lars; Blinova, Ksenia; Mason, Jay W; Weeke, Peter; Behr, Elijah R; Roden, Dan M; Woosley, Ray; Kosova, Gulum; Rosenberg, Michael A; Newton-Cheh, Christopher

2017-04-04

Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, crossover trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine, and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate-corrected QT (QTc) versus drug concentration. The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide ( r =0.55; 95% confidence interval, 0.09-0.81; P =0.02), 23% in response to quinidine ( r =0.48; 95% confidence interval, -0.03 to 0.79; P =0.06), and 27% in response to ranolazine ( r =0.52; 95% confidence interval, 0.05-0.80; P =0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared with 771 controls ( r 2 =12%, P =1×10 -7 ). We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to

Glucose ingestion causes cardiac repolarization disturbances in type 1 long QT syndrome patients and healthy subjects.

PubMed

Hyltén-Cavallius, Louise; Iepsen, Eva W; Christiansen, Michael; Graff, Claus; Linneberg, Allan; Pedersen, Oluf; Holst, Jens J; Hansen, Torben; Torekov, Signe S; Kanters, Jørgen K

2017-08-01

Both hypoglycemia and severe hyperglycemia constitute known risk factors for cardiac repolarization changes potentially leading to malignant arrhythmias. Patients with loss of function mutations in KCNQ1 are characterized by long QT syndrome (LQTS) and may be at increased risk for glucose-induced repolarization disturbances. The purpose of this study was to test the hypothesis that KCNQ1 LQTS patients are at particular risk for cardiac repolarization changes during the relative hyperglycemia that occurs after an oral glucose load. Fourteen KCNQ1 LQTS patients and 28 control participants matched for gender, body mass index, and age underwent a 3-hour oral 75-g glucose tolerance test with ECGs obtained at 7 time points. Fridericia corrected QT interval (QTcF), Bazett corrected QT interval (QTcB), and the Morphology Combination Score (MCS) were calculated. QTc and MCS increased in both groups. MCS remained elevated until 150 minutes after glucose ingestion, and the maximal change from baseline was larger among KCNQ1 LQTS patients compared with control subjects (0.28 ± 0.27 vs 0.15 ± 0.13; P <.05). Relative hyperglycemia induced by ingestion of 75-g glucose caused cardiac repolarization disturbances that were more severe in KCNQ1 LQTS patients compared with control subjects. Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

QT prolongation caused by insulin-induced hypoglycaemia - An interventional study in 119 individuals.

PubMed

Kacheva, Stella; Karges, Beate; Göller, Katrin; Marx, Nikolaus; Mischke, Karl; Karges, Wolfram

2017-01-01

Hypoglycaemia is associated with increased risk of cardiovascular events and mortality in patients with diabetes, but the extent and mechanisms of this link are ill defined. We here prospectively studied cardiac repolarization abnormalities during insulin-induced hypoglycaemia in humans. 119 individuals (69 males, age 47.5±13.4years, range 18-82years) were assessed during hypoglycaemia after the injection of 0.1-0.25units/kg human insulin. Corrected QT intervals (QTc) and QT dispersion (QTd) were calculated from serially recorded twelve lead electrocardiograms, and plasma glucose and other endocrine markers were studied. QTc increased from 415.1±21.9ms (mean±standard deviation) at baseline to 444.9±26.5ms during hypoglycaemia (plasma glucose nadir, 1.6±0.5mmol/L, p=0.001), accompanied by an increase of QTd from 45.0±22.7ms to 64.1±40.0ms (p<0.001). Hypoglycaemia-induced abnormal QTc prolongation (defined as ⩾460ms in females and ⩾450ms in males) occurred in 17% (9/54) of females and 26% (17/65) of males. 97 of 119 of individuals (82%) developed transient hypokalaemia (K + ⩽3.6mmol/L), and plasma epinephrine increased from 220.4±169.5pmol/L at baseline to 2945.6±2421.4pmol/L during hypoglycaemia. Baseline QTc, but not age or gender, was a significant predictor of hypoglycaemia-induced QTc prolongation (p=0.001). Insulin-induced hypoglycaemia frequently causes abnormal QT prolongation and is associated with hypokalaemia and sympathoadrenal activation, thereby increasing the potential risk for ventricular arrhythmias, particularly in individuals with pre-existing high normal QTc. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Effects of 4-aminopyridine on cardiac repolarization, PR interval, and heart rate in patients with spinal cord injury.

PubMed

Isoda, Wakana C; Segal, Jack L

2003-02-01

To determine the effects of 4-aminopyridine (4-AP) on heart rate and PR, QT, and QTc intervals in patients with longstanding spinal cord injury (SCI). Randomized, active-treatment-controlled, dose level-blinded study, with allocation concealed. University-affiliated, tertiary care medical center. Sixty otherwise healthy male and female outpatients with traumatic SCI of more than 1 year's duration. Intervention. Oral administration and dose titration to tolerance of an immediate-release formulation of 4-AP. The PR interval, heart rate, QT interval, and QTc interval obtained from standard 12-lead electrocardiograms (ECGs) at baseline (before administration of 4-AP) and after 1 month of treatment were compared. The QTc intervals were derived by using Bazett's formula (equation) incorporated into standard computerized analyses of 12-lead ECG printouts. The paired t test was performed to test for the significance of differences between means and variances. No statistically significant differences were noted in heart rate or between ECG time intervals measured at baseline and after 1 month of treatment with 4-AP among all patients with SCI or between subgroups stratified by injury level (tetraplegia, paraplegia) or sex. During the 1-month period that 4-AP was administered, the heart rate and PR, QT, and QTc intervals all remained unchanged and stayed well within normal range in comparison to literature-derived control values. 4-Aminopyridine does not appear to influence the length of cardiac time intervals or heart rate and, hence, is unlikely to cause potentially life-threatening ventricular dysrrhythmias when administered long-term and taken orally in dosages of up to 30 mg/day. Specifically, cardiac repolarization (QTc interval) is unaffected in patients with SCI who continuously receive 4-AP for up to 1 month.

Detection of QT prolongation using a novel electrocardiographic analysis algorithm applying intelligent automation: prospective blinded evaluation using the Cardiac Safety Research Consortium electrocardiographic database.

PubMed

Green, Cynthia L; Kligfield, Paul; George, Samuel; Gussak, Ihor; Vajdic, Branislav; Sager, Philip; Krucoff, Mitchell W

2012-03-01

The Cardiac Safety Research Consortium (CSRC) provides both "learning" and blinded "testing" digital electrocardiographic (ECG) data sets from thorough QT (TQT) studies annotated for submission to the US Food and Drug Administration (FDA) to developers of ECG analysis technologies. This article reports the first results from a blinded testing data set that examines developer reanalysis of original sponsor-reported core laboratory data. A total of 11,925 anonymized ECGs including both moxifloxacin and placebo arms of a parallel-group TQT in 181 subjects were blindly analyzed using a novel ECG analysis algorithm applying intelligent automation. Developer-measured ECG intervals were submitted to CSRC for unblinding, temporal reconstruction of the TQT exposures, and statistical comparison to core laboratory findings previously submitted to FDA by the pharmaceutical sponsor. Primary comparisons included baseline-adjusted interval measurements, baseline- and placebo-adjusted moxifloxacin QTcF changes (ddQTcF), and associated variability measures. Developer and sponsor-reported baseline-adjusted data were similar with average differences <1 ms for all intervals. Both developer- and sponsor-reported data demonstrated assay sensitivity with similar ddQTcF changes. Average within-subject SD for triplicate QTcF measurements was significantly lower for developer- than sponsor-reported data (5.4 and 7.2 ms, respectively; P < .001). The virtually automated ECG algorithm used for this analysis produced similar yet less variable TQT results compared with the sponsor-reported study, without the use of a manual core laboratory. These findings indicate that CSRC ECG data sets can be useful for evaluating novel methods and algorithms for determining drug-induced QT/QTc prolongation. Although the results should not constitute endorsement of specific algorithms by either CSRC or FDA, the value of a public domain digital ECG warehouse to provide prospective, blinded comparisons of ECG

Detection of QT prolongation using a novel ECG analysis algorithm applying intelligent automation: Prospective blinded evaluation using the Cardiac Safety Research Consortium ECG database

PubMed Central

Green, Cynthia L.; Kligfield, Paul; George, Samuel; Gussak, Ihor; Vajdic, Branislav; Sager, Philip; Krucoff, Mitchell W.

2013-01-01

Background The Cardiac Safety Research Consortium (CSRC) provides both “learning” and blinded “testing” digital ECG datasets from thorough QT (TQT) studies annotated for submission to the US Food and Drug Administration (FDA) to developers of ECG analysis technologies. This manuscript reports the first results from a blinded “testing” dataset that examines Developer re-analysis of original Sponsor-reported core laboratory data. Methods 11,925 anonymized ECGs including both moxifloxacin and placebo arms of a parallel-group TQT in 191 subjects were blindly analyzed using a novel ECG analysis algorithm applying intelligent automation. Developer measured ECG intervals were submitted to CSRC for unblinding, temporal reconstruction of the TQT exposures, and statistical comparison to core laboratory findings previously submitted to FDA by the pharmaceutical sponsor. Primary comparisons included baseline-adjusted interval measurements, baseline- and placebo-adjusted moxifloxacin QTcF changes (ddQTcF), and associated variability measures. Results Developer and Sponsor-reported baseline-adjusted data were similar with average differences less than 1 millisecond (ms) for all intervals. Both Developer and Sponsor-reported data demonstrated assay sensitivity with similar ddQTcF changes. Average within-subject standard deviation for triplicate QTcF measurements was significantly lower for Developer than Sponsor-reported data (5.4 ms and 7.2 ms, respectively; p<0.001). Conclusion The virtually automated ECG algorithm used for this analysis produced similar yet less variable TQT results compared to the Sponsor-reported study, without the use of a manual core laboratory. These findings indicate CSRC ECG datasets can be useful for evaluating novel methods and algorithms for determining QT/QTc prolongation by drugs. While the results should not constitute endorsement of specific algorithms by either CSRC or FDA, the value of a public domain digital ECG warehouse to

Analysis of Relationship between Levofloxacin and Corrected QT Prolongation Using a Clinical Data Warehouse

PubMed Central

Park, Man Young; Kim, Eun Yeob; Lee, Young Ho; Kim, Woojae; Kim, Ku Sang; Sheen, Seung Soo; Lim, Hong Seok

2011-01-01

Objective The aim of this study was to examine whether or not levofloxacin has any relationship with QT prolongation in a real clinical setting by analyzing a clinical data warehouse of data collected from different hospital information systems. Methods Electronic prescription data and medical charts from 3 different hospitals spanning the past 9 years were reviewed, and a clinical data warehouse was constructed. Patients who were both administrated levofloxacin and given electrocardiograms (ECG) were selected. The correlations between various patient characteristics, concomitant drugs, corrected QT (QTc) prolongation, and the interval difference in QTc before and after levofloxacin administration were analyzed. Results A total of 2,176 patients from 3 different hospitals were included in the study. QTc prolongation was found in 364 patients (16.7%). The study revealed that age (OR 1.026, p < 0.001), gender (OR 0.676, p = 0.007), body temperature (OR 1.267, p = 0.024), and cigarette smoking (OR 1.641, p = 0.022) were related with QTc prolongation. After adjusting for related factors, 12 drugs concomitant with levofloxacin were associated with QTc prolongation. For patients who took ECGs before and after administration of levofloxacin during their hospitalization (n = 112), there was no significant difference in QTc prolongation. Conclusions The age, gender, body temperature, cigarette smoking and various concomitant drugs might be related with QTc prolongation. However, there was no definite causal relationship or interaction between levofloxacin and QTc prolongation. Alternative surveillance methods utilizing the massive accumulation of electronic medical data seem to be essential to adverse drug reaction surveillance in future. PMID:21818458

Iron Metabolism Genes, Low-Level Lead Exposure, and QT Interval

PubMed Central

Park, Sung Kyun; Hu, Howard; Wright, Robert O.; Schwartz, Joel; Cheng, Yawen; Sparrow, David; Vokonas, Pantel S.; Weisskopf, Marc G.

2009-01-01

Background Cumulative exposure to lead has been shown to be associated with depression of electrocardiographic conduction, such as QT interval (time from start of the Q wave to end of the T wave). Because iron can enhance the oxidative effects of lead, we examined whether polymorphisms in iron metabolism genes [hemochromatosis (HFE), transferrin (TF) C2, and heme oxygenase-1 (HMOX-1)] increase susceptibility to the effects of lead on QT interval in 613 community-dwelling older men. Methods We used standard 12-lead electrocardiograms, K-shell X-ray fluorescence, and graphite furnace atomic absorption spectrometry to measure QT interval, bone lead, and blood lead levels, respectively. Results A one-interquartile-range increase in tibia lead level (13 μg/g) was associated with a 11.35-msec [95% confidence interval (CI), 4.05–18.65 msec] and a 6.81-msec (95% CI, 1.67–11.95 msec) increase in the heart-rate–corrected QT interval among persons carrying long HMOX-1 alleles and at least one copy of an HFE variant, respectively, but had no effect in persons with short and middle HMOX-1 alleles and the wild-type HFE genotype. The lengthening of the heart-rate–corrected QT interval with higher tibia lead and blood lead became more pronounced as the total number (0 vs. 1 vs. ≥2) of gene variants increased (tibia, p-trend = 0.01; blood, p-trend = 0.04). This synergy seems to be driven by a joint effect between HFE variant and HMOX-1 L alleles. Conclusion We found evidence that gene variants related to iron metabolism increase the impacts of low-level lead exposure on the prolonged QT interval. This is the first such report, so these results should be interpreted cautiously and need to be independently verified. PMID:19165391

Pyrilamine-induced prolonged QT interval in adolescent with drug overdose.

PubMed

Paudel, Govinda; Syed, Muhammad; Kalantre, Sarika; Sharma, Jayendra

2011-10-01

The widespread availability of antihistamines in many over-the-counter preparations can lead to significant hazard to the public because of their possible link to potential ventricular arrhythmias secondary to prolongation of QT interval. The effect can be further compounded by the use of other commonly used medications such as macrolides, antifungal agents, antipsychotics, and other antihistamine-containing preparations. The effect of antihistamines on QT interval is not a class effect but is unique to certain medications. Pyrilamine, a first-generation antihistaminic agent, is considered safe as there are no reports regarding its cardiac toxicity available in literature. We report a case of an adolescent with prolonged QT interval after an overdose of pyrilamine.

Increased QT interval variability index in acute alcohol withdrawal.

PubMed

Bär, Karl-Jürgen; Boettger, Michael Karl; Koschke, Mandy; Boettger, Silke; Grotelüschen, Marei; Voss, Andreas; Yeragani, Vikram K

2007-07-10

Acute alcohol withdrawal is associated with increased cardiovascular mortality, most likely due to cardiac arrhythmias. As the QT interval reflects the most critical phase for the generation of reentry and thus for arrhythmia, we examined QT variability in patients suffering from acute alcohol withdrawal. High resolution electrocardiographic recordings were performed in 18 male unmedicated patients suffering from acute alcohol withdrawal, 18 matched controls and 15 abstained alcoholics. From these, parameters of beat-to-beat heart rate and QT variability such as approximate entropy and QT variability index (QTvi) were calculated. Measures were correlated with the severity of withdrawal symptoms and with serum electrolyte concentrations. Heart rate and QTvi were significantly increased in acute alcohol withdrawal. Abstained alcoholics did not significantly differ from controls. While QTvi correlated with the severity of alcohol withdrawal symptoms, the mean QT interval duration showed an inverse relationship with serum potassium concentrations. Our data indicate increased QT variability and thus increased repolarization lability in acute alcohol withdrawal. This might add to the elevated risk for serious cardiac arrhythmias. In part, these changes might be related to increased cardiac sympathetic activity or low potassium, thus suggesting the latter as possible targets for adjuvant pharmacological therapy during withdrawal.

Evaluation of Electrocardiographic T-peak to T-end Interval in Subjects with Increased Epicardial Fat Tissue Thickness.

PubMed

Kaplan, Ozgur; Kurtoglu, Ertugrul; Nar, Gokay; Yasar, Erdogan; Gozubuyuk, Gokhan; Dogan, Cem; Boz, Ahmet Ugur; Hidayet, Sıho; Pekdemir, Hasan

2015-12-01

The association between periatrial adiposity and atrial arrhythmias has been shown in previous studies. However, there are not enough available data on the association between epicardial fat tissue (EFT) thickness and parameters of ventricular repolarization. Thus, we aimed to evaluate the association of EFT thickness with indices of ventricular repolarization by using T-peak to T-end (Tp-e) interval and Tp-e/QT ratio. The present study included 50 patients whose EFT thickness ≥ 9 mm (group 1) and 40 control subjects with EFT thickness < 9 mm (group 2). Transthoracic echocardiographic examination was performed in all participants. QT parameters, Tp-e intervals and Tp-e/QT ratio were measured from the 12-lead electrocardiogram. QTd (41.1 ± 2.5 vs 38.6 ± 3.2, p < 0.001) and corrected QTd (46.7 ± 4.7 vs 43.7 ± 4, p = 0.002) were significantly higher in group 1 when compared to group 2. The Tp-e interval (76.5 ± 6.3, 70.3 ± 6.8, p < 0.001), cTp-e interval (83.1 ± 4.3 vs. 76±4.9, p < 0.001), Tp-e/QT (0.20 ± 0.02 vs. 0.2 ± 0.02, p < 0.001) and Tp-e/QTc ratios (0.2 ± 0.01 vs. 0.18 ± 0.01, p < 0.001) were increased in group 1 in comparison to group 2. Significant positive correlations were found between EFT thickness and Tp-e interval (r = 0.548, p < 0.001), cTp-e interval (r = 0.259, p = 0.01), and Tp-e/QT (r = 0.662, p < 0.001) and Tp-e/QTc ratios (r = 0.560, p < 0.001). The present study shows that Tp-e and cTp-e interval, Tp-e/QT and Tp-e/QTc ratios were increased in subjects with increased EFT, which may suggest an increased risk of ventricular arrhythmia.

Emotional stress as a cause of syncope and torsade de pointes in patients with long QT syndrome.

PubMed

Vukmirović, Mihailo; Vukmirović, Irena Tomašević; Angelkov, Lazar; Vukmirović, Filip

2015-02-01

Long QT syndrome (LQTS) is a disorder of myocardial repolarization characterized by the prolongation of QT interval and high risk propensity of torsade de pointes (TdP) that can lead to syncope, cardiac arrest and sudden death. Episodes may be provoked by various stimuli depending on the type of the condition. A 25-year-old famele patient was hospitalized due to syncope that occurred immediately after her solo concert, first time in her life. The patient studied solo singing and after intensive preparations the first solo concert was organized. Electrocardiography (ECG) on admission registered frequent ventricular premature beats (VES), followed by polymorphic ventricular tachycardia--TdP that degenerated into ventricular fibrilation (VF). After immediate cardioversion magnesium and beta-blockers were administered. TdP was registered again several times preceded by VES. The corrected QT interval (QTc) was 516 msec. For secondary prevention of sudden cardiac death, a cardioverter defibrillator was implanted, and beta-blockers continued. After a 1-year follow-up there were no recurrent episodes of TdP, and measured QTc was reduced to 484 msec. Patients with syncope following intensive emotional stress should be evaluated for malignant arrhythmias in the context of LQTS.

Medical toxicologists' practice patterns regarding drug-induced QT prolongation in overdose patients: a survey in the United States of America, Europe, and Asia Pacific region.

PubMed

Othong, Rittirak; Devlin, John J; Kazzi, Ziad N

2015-05-01

To describe practice patterns of medical toxicologists in the United States of America (USA), Europe, and Asia Pacific Region regarding management of drug induced QT prolongation and torsades de pointes in overdose. A survey was developed to assess current practice patterns and consistency with guidelines published by the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC). It was reviewed by our department research committee and the American College of Medical Toxicology (ACMT). The ACMT, European Association of Poisons Centres and Clinical Toxicologists, and Asia Pacific Association of Medical Toxicology electronically disseminated the survey to their physician members in the USA, Europe and Asia Pacific Region. The overall response rate was 37% (229/617) (36% USA; 32% Europe; 52% Asia Pacific Region). Twelve toxicologists from Asia Pacific Region and Europe used the QT nomogram (Australia-5, New Zealand-1, United Kingdom-1) or QT alone (France-1, Russia-1, Romania-1, Germany-1, Philippines-1), in lieu of the corrected QT (QTc) to determine risks of developing torsades de pointes. Because only those who used QTc could proceed through the remainder of the survey, only 217 could do so. Approximately half of the respondents (52%) did not calculate QTc manually and based decisions on the electrocardiogram machines automated measurement. For those who corrected the QT interval themselves, the most common formula used was Bazett's (40%). There is great variation in the QTc value considered prolonged. Most responders considered QTc greater than 450 ms in men (28%) and 460 ms in women (25%) to be prolonged. Interestingly, approximately 15% of participants did not consider the QTc prolonged until it exceeded 500 ms in both men and women. Given an overdose scenario of a male patient with a QTc of 560 ms, heart rate of 90 beats/minute, 59% would not recommend administering intravenous magnesium sulfate. Forty

Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis.

PubMed

Winbo, Annika; Stattin, Eva-Lena; Westin, Ida Maria; Norberg, Anna; Persson, Johan; Jensen, Steen M; Rydberg, Annika

2017-07-18

Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1AP sequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations. This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs. A substantial variance in mean QTc was seen in genotype positives 476 ± 36 ms (Y111C 483 ± 34 ms; R518* 462 ± 34 ms) and genotype negatives 433 ± 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, +18 ms (p = 0.0007) and +17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0.001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with

A modeling and simulation approach to characterize methadone QT prolongation using pooled data from five clinical trials in MMT patients.

PubMed

Florian, J; Garnett, C E; Nallani, S C; Rappaport, B A; Throckmorton, D C

2012-04-01

Pharmacokinetic (PK)-pharmacodynamic modeling and simulation were used to establish a link between methadone dose, concentrations, and Fridericia rate-corrected QT (QTcF) interval prolongation, and to identify a dose that was associated with increased risk of developing torsade de pointes. A linear relationship between concentration and QTcF described the data from five clinical trials in patients on methadone maintenance treatment (MMT). A previously published population PK model adequately described the concentration-time data, and this model was used for simulation. QTcF was increased by a mean (90% confidence interval (CI)) of 17 (12, 22) ms per 1,000 ng/ml of methadone. Based on this model, doses >120 mg/day would increase the QTcF interval by >20 ms. The model predicts that 1-3% of patients would have ΔQTcF >60 ms, and 0.3-2.0% of patients would have QTcF >500 ms at doses of 160-200 mg/day. Our predictions are consistent with available observational data and support the need for electrocardiogram (ECG) monitoring and arrhythmia risk factor assessment in patients receiving methadone doses >120 mg/day.

A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anesthetized dogs.

PubMed

van der Linde, H; Van de Water, A; Loots, W; Van Deuren, B; Lu, H R; Van Ammel, K; Peeters, M; Gallacher, D J

2005-01-01

Instability of QT duration is a marker to predict Torsade de Pointes (TdP) associated with both congenital and drug-induced long QT syndrome. We describe a new method for the quantification of instability of repolarization. Female, adult beagle dogs anesthetized with a potent morphinomimetic were treated with either solvent (n=7) or dofetilide (n=7). Poincaré plots with QT(n) versus QT(n+1) were constructed to visualize the beat-to-beat variation in QT intervals from the lead II ECG. Short-term instability (STI), long-term instability (LTI) and total instability (TI) were quantified by calculating the distances of 30 consecutive data-points from the x and y-coordinate to the "centre of gravity" of the data cluster. Dofetilide at 0.0025 to 0.04 mg/kg i.v. (plasma concentrations of 4+/-0.6 to 41+/-2.7 ng/ml), dose-dependently prolonged QT and QTcV (at 0.04 mg/kg i.v.: QT: 280+/-ms versus 236+/-5 ms with solvent; p<0.05 and QTcV: 290+/-9 ms versus 252+/-4 ms with solvent; p<0.05). Concomitantly, the compound induced an increase in the instability parameters in a similar dose-dependent manner (at 0.04 mg/kg i.v.: TI: 6.8+/-0.9 ms versus 1.7+/-0.3 ms; p<0.05, LTI: 3.6+/-0.5 ms versus 1.0+/-0.2 ms; p<0.05 and STI: 4.2+/-0.6 ms versus 1.0+/-0.2 ms; p<0.05). The increases induced by dofetilide were associated with a high incidence of early afterdepolarizations (EADs) in the endocardial monophasic action potential (in 6 out of the 7 compound-treated animals versus 0 out of the 7 solvent animals; p<0.05). Quantification of beat-to-beat QT instability by our method clearly detects changes in short-term, long-term and total instability induced by dofetilide, already at pre-arrhythmic doses. Dofetilide administration to anesthetized dogs prolongs ventricular repolarization, concomitantly increases beat-to-beat QT instability and induces early after depolarizations (EADs). As such, the use of these parameters in this in vivo model shows clear potential for risk identification

Obstructive sleep apnea is associated with increased QT corrected interval dispersion: the effects of continuous positive airway pressure.

PubMed

Bilal, Nagihan; Dikmen, Nursel; Bozkus, Fulsen; Sungur, Aylin; Sarica, Selman; Orhan, Israfil; Samur, Anil

2017-03-31

Severe obstructive sleep apnea (OSA) is associated with increased QT corrected interval dispersion (QTcd) and continuous positive airway pressure (CPAP) is thought to improve this arrhythmogenic marker. The aim of the study was to determine the decrease of ratio of cardiovascular risk in patients with obstructive sleep apnea. The study included 65 patients with severe OSA who had an apnea-hypopnea index (AHI) score of >30. Each patient underwent 12-channel electrocardiogram (ECG) monitoring and polysomnography. Patients with an AHI score of <5 were used as the control group. The control group also underwent ECG monitoring and polysomnography testing. The QTcd levels of both groups were calculated. Three months after CPAP treatment, ECG recordings were obtained from the 65 patients with severe OSA again, and their QTcd values were calculated. There were 44 male and 21 female patients with severe OSA syndrome. The age, gender, body mass index, initial saturation, minimum saturation, average saturation, and desaturation index were determined in both groups. The QTc intervals of the OSA patients (62.48±16.29ms) were significantly higher (p=0.001) than those of the control group (29.72±6.30ms). There were statistically significant differences between the QTc values before and after the CPAP treatment, with pretreatment QTc intervals of 62.48±16.29ms and 3-month post-treatment values of 41.42±16.96ms (p=0.001). There was a positive and significant correlation between QTcd periods and the AHI and hypopnea index (HI) in OSA patients (p=0.001; r=0.71; p=0.001; r=0.679, respectively). CPAP treatment reduced the QTcd in patients with severe OSA. In addition, shortening the QTcd periods in patients with severe OSA may reduce their risk of arrhythmias and cardiovascular disease. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

[Risk management of QT-prolonging drugs by community pharmacists using a mobile electrocardiograph].

PubMed

Shinozaki, Kohki

2010-11-01

Prolongation of the QT interval is associated with a high risk of serious arrhythmia, i.e., torsades de pointes (TdP). However, in many cases, the QT-prolonging drug(s) is prescribed without performing a thorough check-up of the patient's condition, especially an electrocardiogram. In addition to patient interview, we used an electrocardiogram obtained with a mobile electrocardiograph (RMH-ECG) in a community pharmacy in order to improve the risk management for QT-prolonging drugs. A comparison of the results obtained using RMH-ECG (modified I) and 12-lead ECG (I) revealed that both corrected QT (QTc) values were almost identical, and the correlation coefficient was 0.96. In one month, 5 of 948 patients who visited our pharmacy and continuously took QT-prolonging drugs had additional risk factors for TdP (advanced age, female, and drug-drug interaction). We monitored the QT interval of one of these patients. She had received erythromycin for 19 months along with other drugs metabolized by a P450 (CYP3A4); benidipine and prednisolone (for over 2 years), and tacrolimus (for 13 weeks). Three RMH-ECG tests at every 2 weeks revealed that QTcs were normal (0.43-0.45 s); therefore, we dispensed drugs without any change in the prescription. Approximately 1 in 1200 individuals has a prolonged QT interval without any subjective symptoms, and the time window of drug-induced TdP is considered to be from several hours to months after taking these drugs. Therefore, we think that an ECG test should be performed in community pharmacies before dispensing QT-prolonging drugs and that the QT interval should be monitored.

Circadian rhythm in QT interval is preserved in mice deficient of potassium channel interacting protein 2.

PubMed

Gottlieb, Lisa A; Lubberding, Anniek; Larsen, Anders Peter; Thomsen, Morten B

2017-01-01

Potassium Channel Interacting Protein 2 (KChIP2) is suggested to be responsible for the circadian rhythm in repolarization duration, ventricular arrhythmias, and sudden cardiac death. We investigated the hypothesis that there is no circadian rhythm in QT interval in the absence of KChIP2. Implanted telemetric devices recorded electrocardiogram continuously for 5 days in conscious wild-type mice (WT, n = 9) and KChIP2 -/- mice (n = 9) in light:dark periods and in complete darkness. QT intervals were determined from all RR intervals and corrected for heart rate (QT 100 = QT/(RR/100) 1/2 ). Moreover, QT intervals were determined from complexes within the RR range of mean-RR ± 1% in the individual mouse (QT mean-RR ). We find that RR intervals are 125 ± 5 ms in WT and 123 ± 4 ms in KChIP2 -/- (p = 0.81), and QT intervals are 52 ± 1 and 52 ± 1 ms, respectively(p = 0.89). No ventricular arrhythmias or sudden cardiac deaths were observed. We find similar diurnal (light:dark) and circadian (darkness) rhythms of RR intervals in WT and KChIP2 -/- mice. Circadian rhythms in QT 100 intervals are present in both groups, but at physiological small amplitudes: 1.6 ± 0.2 and 1.0 ± 0.3 ms in WT and KChIP2 -/- , respectively (p = 0.15). A diurnal rhythm in QT 100 intervals was only found in WT mice. QT mean-RR intervals display clear diurnal and circadian rhythms in both WT and KChIP2 -/- . The amplitude of the circadian rhythm in QT mean-RR is 4.0 ± 0.3 and 3.1 ± 0.5 ms in WT and KChIP2 -/- , respectively (p = 0.16). In conclusion, KChIP2 expression does not appear to underlie the circadian rhythm in repolarization duration.

Evidence for a crucial modulating role of the sodium channel in the QTc prolongation related to antipsychotics.

PubMed

Silvestre, Jordi S; O'Neill, Michael F; Prous, Josep R

2014-04-01

Blockade of the cardiac hERG channel is recognized as the main mechanism underlying the QT prolongation induced by many classes of drugs, including antipsychotics. However, antipsychotics interact with a variety of other pharmacological targets that could also modulate cardiac function. The present study aims to identify those key factors involved in the QT prolongation induced by antipsychotics. The interactions of 28 antipsychotics were measured on a variety of pharmacological targets. Binding affinity (K(i)), functional channel blockade (IC₅₀), and the corresponding ratios to total and free plasma drug concentration were compared with the corrected QT changes (QTc) associated with the therapeutic use of these drugs by multivariable linear regression analysis to determine the best predictors of QTc. Besides confirming hERG as the primary predictor of QTc, all analyses consistently show the concomitant involvement of Na(V)1.5 channel as modulating factor of the QTc related to hERG blockade. In particular, the hERG/Na(V)1.5 ratio explains the 57% of the overall QTc variability associated with antipsychotics. Since it is known that inhibition of late I Na could offset the dysfunctional effects of hERG blockade, we hypothesize the inhibition of late I(Na) as a crucial compensatory mechanism of the QTc associated with antipsychotics and hence an important factor to consider concomitantly with hERG blockade to appraise the arrhythmogenic risk of these drugs more accurately.

Induction of autoimmune response to the extracellular loop of the HERG channel pore induces QTc prolongation in guinea‐pigs

PubMed Central

Fabris, Frank; Yue, Yuankun; Qu, Yongxia; Chahine, Mohamed; Sobie, Eric; Lee, Peng; Wieczorek, Rosemary; Jiang, Xian‐Cheng; Capecchi, Pier‐Leopoldo; Laghi‐Pasini, Franco; Lazzerini, Pietro‐Enea

2016-01-01

. Inhibition of the HERG channel was assessed by electrophysiology and by computational modelling of the human ventricular action potential. The ELISA results revealed the presence of high titres of E‐pore peptide Abs and significant QTc prolongation after immunization. High reactivity to E‐pore peptide was found using anti‐SSA/Ro Ab‐positive sera from patients with QTc prolongation. Histological data showed no evidence of fibrosis in immunized hearts. Simulations of simultaneous inhibition of repolarizing currents by anti‐SSA/Ro Ab‐positive sera showed the predominance of the HERG channel in controlling action potential duration and the QT interval. These results are the first to demonstrate that inhibitory Abs to the HERG E‐pore region induce QTc prolongation in immunized guinea‐pigs by targeting the HERG channel independently from fibrosis. The reactivity of anti‐SSA/Ro Ab‐positive sera from patients with connective tissue diseases with the E‐pore peptide opens novel pharmacotherapeutic avenues in the diagnosis and management of autoimmune‐associated QTc prolongation. PMID:27296897

BPC 157 counteracts QTc prolongation induced by haloperidol, fluphenazine, clozapine, olanzapine, quetiapine, sulpiride, and metoclopramide in rats.

PubMed

Strinic, Dean; Belosic Halle, Zeljka; Luetic, Kresimir; Nedic, Ana; Petrovic, Igor; Sucic, Mario; Zivanovic Posilovic, Gordana; Balenovic, Dijana; Strbe, Sanja; Udovicic, Mario; Drmic, Domagoj; Stupnisek, Mirjana; Lovric Bencic, Martina; Seiwerth, Sven; Sikiric, Predrag

2017-10-01

Commonly, neuroleptics and prokinetics induce a prolonged QTc interval. In this study, stable gastric pentadecapeptide BPC 157 counteracts the prolongation of the QTc interval in Wistar rats that underwent daily administration of dopamine neuroleptics or prokinetics. Previously, in rats and mice, BPC 157 counteracted neuroleptic-induced catalepsy and gastric ulcers. To counteract neuroleptic- or prokinetic-induced prolongation of the QTc interval, rats were given a BPC 157 regimen once daily over seven days (10μg, 10ng/kg ip) immediately after each administrations of haloperidol (0.625, 6.25, 12.5, and 25.0mg/kg ip), fluphenazine (0.5, 5.0mg/kg ip), clozapine (1.0, 10.0mg/kg ip), quetiapine (1.0, 10.0mg/kg ip), sulpiride (1.6, 16.0mg/kg ip), metoclopramide (2.5, 25.0mg/kg ip) or (1.0, 10.0mg/kg ip). Controls simultaneously received saline (5ml/kg ip). To assess the ECG presentation before and after neuroleptic/prokinetic medication, the assessment was at 1, 2, 3, 4, 5, 10, 15, 20 and 30min (first administration) as well as at 30min, 60min and 24h (first administration and subsequent administrations) and the ECG recording started prior to drug administration. Since very early, a prolonged QTc interval has been continually noted with haloperidol, fluphenazine, clozapine, olanzapine, quetiapine, sulpiride, and metoclopramide in rats as a central common effect not seen with domperidone. Consistent counteraction appears with the stable gastric pentadecapeptide BPC 157. Thus, BPC 157 rapidly and permanently counteracts the QTc prolongation induced by neuroleptics and prokinetics. Pentadecapeptide BPC 157 is suited for counteracting a prolonged QT interval. Copyright © 2017 Elsevier Inc. All rights reserved.

The prevalence and significance of a short QT interval in 18,825 low-risk individuals including athletes.

PubMed

Dhutia, Harshil; Malhotra, Aneil; Parpia, Sameer; Gabus, Vincent; Finocchiaro, Gherardo; Mellor, Greg; Merghani, Ahmed; Millar, Lynne; Narain, Rajay; Sheikh, Nabeel; Behr, Elijah R; Papadakis, Michael; Sharma, Sanjay

2016-01-01

The short QT syndrome is a cardiac channelopathy characterised by accelerated repolarisation which manifests as a short QT interval on the ECG. The definition of a short QT interval is debated, ranging from <390 to ≤320 ms, and its clinical significance in healthy young individuals is unknown. We assessed the prevalence and medium-term significance of an isolated short QT interval in a diverse young British population. Between 2005 and 2013, 18 825 apparently healthy people aged 14-35 years underwent cardiovascular evaluation with history, physical examination and ECG. QT intervals were measured by cardiologists using 4 recommended guidelines (Seattle 2013, Heart Rhythm Society 2013, European Society of Cardiology 2010 and American Heart Association 2009). The prevalence of a short QT interval was 0.1% (26 patients, ≤320 ms), 0.2% (44 patients, ≤330 ms), 7.9% (1478 patients, <380 ms), 15.8% (2973 patients, <390 ms). Male gender and Afro-Caribbean ethnicity had the strongest association with short QT intervals. Athletes had shorter QT intervals than non-athletes but athletic status did not predict short QT intervals. Individuals with short QT intervals ≤320 ms did not report syncope or a sinister family history, and during a follow-up period of 5.3±1.2 years, there were no deaths in this group. The prevalence of a short QT interval depends on the recommended cut-off value. Even at values ≤320 ms, there was an excellent medium-term prognosis among 14 people followed. We conclude that a definition of ≤320 ms is realistic to prevent overdiagnosis and excessive investigations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

ICH E14 Q & A (R1) document: perspectives on the updated recommendations on thorough QT studies.

PubMed

Shah, Rashmi R; Morganroth, Joel

2013-04-01

The International Conference on Harmonization (ICH) guidance ICH E14 provides recommendations, focusing on a clinical 'thorough QT/QTc (TQT) study', to evaluate the QT liability of a drug during its development. An Implementation Working Group (IWG) was also established to assist the sponsors with any uncertainties and clarify any ambiguities. In April 2012, the IWG updated its June 2008 version of the Questions and Answers document to address additional issues. These include the gender of the study population, a reasonable approach to evaluating QTc changes in late stage clinical development and the recommended approach to correcting the measured QT interval. This commentary provides our observations and, when appropriate, recommendations, on these issues. We review briefly evidence that suggests that (i) the greater QT effect observed in females is not entirely related to differences in drug exposure and (ii) the Fridericia correction of measured QT interval is adequate for a majority of TQT studies. Until further evidence suggests otherwise, we recommend balanced gender representation in TQT studies, unless warranted otherwise, and for positive studies, subgroup analysis of key data by common demographic variables including the gender and ethnicity. We provide a general scheme for ECG monitoring in late phase clinical trials and consider that while intensive monitoring and centralized reading of ECGs in late phase clinical trials is the norm when a TQT study is positive, there are other circumstances that also call for high quality ECG reading. Therefore, locally read ECGs should only be acceptable as long as accurate high quality ECG data can be guaranteed. © 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Prolonged Tp-e Interval in Down Syndrome Patients with Congenitally Normal Hearts.

PubMed

Kucuk, Mehmet; Karadeniz, Cem; Ozdemir, Rahmi; Meşe, Timur

2018-03-25

Heterogeneity of ventricular repolarization has been assessed by using the QT dispersion in Down syndrome (DS) patients with congenitally normal hearts. However, novel repolarization indexes, the Tp-e interval and Tp-e/QT ratio, have not previously been evaluated in these patients. The aim of this study was to evaluate the Tp-e interval and Tp-e/QT ratio in DS patients without congenital heart defects. Twelve-lead surface electrocardiograms of 160 DS patients and 110 age- and sex-matched healthy controls were used to evaluate and compare the Tp-e interval, Tp-e dispersion, and Tp-e/QT ratio. Heart rate, Tp-e interval, Tp-e dispersion, Tp-e/QT and Tp-e/QTc ratios were significantly higher in DS group than in the controls. Myocardial repolarization indexes in DS patients with congenitally normal hearts were found to be prolonged compared to those in normal controls. Further evaluation is warranted to reveal a relationship between prolonged repolarization indexes and arrhythmic events in these patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Prolonged QT interval in a man with anorexia nervosa

PubMed Central

Macías-Robles, María Dolores; Perez-Clemente, Ana María; Maciá-Bobes, Carmen; Alvarez-Rueda, María Asunción; Pozo-Nuevo, Sergio

2009-01-01

Anorexia nervosa is an eating disorder characterized by the avoidance of food intake, which usually leads to a weight loss. Cardiac co-morbility is common and we can find sometimes a mass loss from the left ventricle, which can be seen by echocardiography. But the commonest complications are rhythm variations, typically bradycardia with a prolonged QT interval in up to a 40% of the cases, which altogether elevates ventricular tachycardia and sudden death risk. We present the case of a male who was diagnosed with anorexia nervosa and developed asthenia, a long QT interval and also a severe both hypokalaemia and hypomagnesaemia. We intend to discuss the pathogenic paths as well as prophylactic and therapeutic measures to this potentially-lethal pathology. PMID:19646241

Effects of atypical antipsychotic drugs on QT interval in patients with mental disorders

PubMed Central

Aronow, Wilbert S.

2018-01-01

Background Drug-induced QT prolongation is associated with higher risk of cardiac arrhythmias and cardiovascular mortality. We investigated the effects of atypical antipsychotic drugs on QT interval in children and adults with mental disorders. Methods We conducted random-effects direct frequentist meta-analyses of aggregate data from randomized controlled trials (RCT) and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to October 2017 identified studies that examined aripiprazole, quetiapine, risperidone, olanzapine, ziprasidone and brexpiprazole. Results Low quality evidence suggests that aripiprazole (four meta-analyses and twelve RCTs), brexpiprazole (one systematic review and four RCTs) or olanzapine (five meta-analyses and twenty RCTs) do not increase QT interval. Low quality evidence suggests that ziprasidone (five meta-analyses and 11 RCTs) increases QT interval and the rates of QT prolongation while risperidone (four meta-analyses, 70 RCTs) and quetiapine (two meta-analyses and seven RCTs) are associated with QT prolongation and greater odds of torsades de pointes ventricular tachycardia especially in cases of drug overdose. Conclusions The main conclusion of our study is that in people with mental disorders and under treatment with atypical antipsychotic drugs, in order to avoid QT prolongation and reduce the risk of ventricular tachycardia clinicians may recommend aripiprazole, brexpiprazole or olanzapine in licensed doses. Long-term comparative safety needs to be established. PMID:29862236

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with ankylosing spondylitis.

PubMed

Acar, Gurkan; Yorgun, Hikmet; Inci, Mehmet Fatih; Akkoyun, Murat; Bakan, Betul; Nacar, Alper Bugra; Dirnak, Imran; Cetin, Gozde Yildirim; Bozoglan, Orhan

2014-03-01

Ankylosing spondylitis (AS) is a chronic multi-systemic inflammatory rheumatic disorder. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using Tp-e interval and Tp-e/QT ratio in patients with AS, and to assess the relation with inflammation. Sixty-two patients with AS and 50 controls were included. Tp-e interval and Tp-e/QT ratio were measured from a 12-lead electrocardiogram, and the Tp-e interval corrected for heart rate. The plasma level of high sensitive C-reactive protein (hsCRP) was measured. These parameters were compared between groups. In electrocardiographic parameters analysis, QT dispersion (QTd) and corrected QTd were significantly increased in AS patients compared to the controls (31.7 ± 9.6 vs 28.2 ± 7.4 and 35.8 ± 11.5 vs 30.6 ± 7.9 ms, P = 0.03 and P = 0.007, respectively). cTp-e interval and Tp-e/QT ratio were also significantly higher in AS patients (92.1 ± 10.2 vs 75.8 ± 8.4 and 0.22 ± 0.02 vs 0.19 ± 0.02 ms, all P values <0.001). cTp-e interval and Tp-e/QT ratio were significantly correlated with hsCRP (r = 0.63, P < 0.001 and r = 0.49, P < 0.001, respectively). Our study revealed that Tp-e interval and Tp-e/QT ratio were increased in AS patients. These electrocardiographic ventricular repolarization indexes were significantly correlated with the plasma level of hsCRP.

The genetics underlying acquired long QT syndrome: impact for genetic screening

PubMed Central

Itoh, Hideki; Crotti, Lia; Aiba, Takeshi; Spazzolini, Carla; Denjoy, Isabelle; Fressart, Véronique; Hayashi, Kenshi; Nakajima, Tadashi; Ohno, Seiko; Makiyama, Takeru; Wu, Jie; Hasegawa, Kanae; Mastantuono, Elisa; Dagradi, Federica; Pedrazzini, Matteo; Yamagishi, Masakazu; Berthet, Myriam; Murakami, Yoshitaka; Shimizu, Wataru; Guicheney, Pascale; Schwartz, Peter J.; Horie, Minoru

2016-01-01

Aims Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors. Methods and results We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated ‘true aLQTS’ (QTc within normal limits) or ‘unmasked cLQTS’ (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in ‘true aLQTS’, KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7–41%] vs. 64% [95% CI 43–82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations. Conclusion A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members. PMID:26715165

A new technique to determine the correlation between the QT interval and heart-rate for control and SIDS babies

NASA Technical Reports Server (NTRS)

Sadeh, D.; Shannon, D. C.; Abboud, S.; Akselrod, S.; Cohen, R. J.

1987-01-01

The ability of the autonomic nervous system to alter the QT interval in response to heart rate changes is essential to cardiovascular control. An accurate way to determine the relation between QT intervals and their corresponding RR intervals is described. A computer algorithm measures the RR intervals using digital filtering and cross-correlating the QRS sections of consecutive waveforms. The QT intervals is calculated by choosing a section of, the ECG that includes the T wave and cross-correlating it with all the consecutive T waves. At least 4000 pairs of QT-RR intervals are computed for each subject and a best fit correlation function determines the relations between the QT and RR intervals. This technique enables to establish a precise correlation between RR and QT in order to distinguish between control and SIDS babies.

Comparison of QTc and Troponin Levels in ST Elevation MIs Compared with Non-ST Elevation MIs.

PubMed

Henrie, Nathan; Harvell, Bryan; Ernst, Amy A; Weiss, Steven J; Oglesbee, Scott; Sarangarm, Dusadee; Hernandez, Lorenzo

2017-03-01

ST elevation myocardial infarctions (STEMIs) and non-ST elevation myocardial infarctions (NSTEMIs) have differences that can be important to differentiate. Our primary hypothesis was that corrected QT (QTc) duration and troponin I levels were higher in STEMIs compared with NSTEMIs. The objective of our study was to compare STEMIs with NSTEMIs for QTc duration and troponin levels. This was a retrospective case-control study of all STEMIs and a random sample of NSTEMIs during a 1-year period. STEMIs were retrieved by searching our electrocardiogram database for all of the cardiology-diagnosed STEMIs. NSTEMIs were found by selecting a randomized sample of all of the patients with a final discharge diagnosis of NSTEMI. Records and electrocardiograms were reviewed for initial troponin I levels and QTc duration. Data extractors were educated formally and a 5% sample was reevaluated by the other extractor as a reliability measure. Data analysis included χ 2 tests and parametric or nonparametric analysis, where appropriate. A logistic regression model was created with variables selected a priori for predictors of STEMIs compared with NSTEMIs. A total of 92 STEMIs and 111 NSTEMIs were evaluated, and interrater reliability showed 90% agreement. Patients with NSTEMIs had significantly longer QTc. Troponin I did not differ on univariate analysis. In a logistic model, Hispanics were more likely than whites to have a STEMI (adjusted odds ratio [AOR] 2.2, 95% confidence interval [CI] 1.09-4.5). An increase in troponin I of 1 was associated with a 7% increase in the AOR of a STEMI (AOR 1.7, 95% CI 1.03-1.12) and an increase in QTc by 10 was associated with a 13% decrease in the AOR of a STEMI (AOR 0.87, 95% CI 0.78-0.93). Patients with NSTEMIs had longer QTc intervals and lower troponin I levels than those with STEMIs.

Usefulness of Electrocardiographic QT Interval to Predict Left Ventricular Diastolic Dysfunction

PubMed Central

Wilcox, Jane E.; Rosenberg, Jonathan; Vallakati, Ajay; Gheorghiade, Mihai; Shah, Sanjiv J.

2013-01-01

Whether a normal electrocardiogram excludes left ventricular (LV) diastolic dysfunction (DD) and whether electrocardiographic parameters are associated with DD is unknown. We therefore sought to investigate the relation between electrocardiographic parameters and DD. We first evaluated 75 consecutive patients referred for echocardiography for clinical suspicion of heart failure (phase 1). Electrocardiography and comprehensive echocardiography were performed on all patients and were analyzed separately in a blinded fashion. Receiver operating characteristic curves and multivariate regression analyses were used to determine which electrocardiographic parameters were most closely associated with DD. Next, we prospectively validated our results in 100 consecutive, unselected patients undergoing echocardiography (phase 2). In phase 1 of our study, the mean age was 59 ± 14 years, 41% were women, 31% had coronary disease, 53% had hypertension, and 25% had diabetes. The mean ejection fraction was 54 ± 15%, and 64% had DD. Of all the electrocardiographic parameters, the QTc interval was most closely associated with DD. QTc was inversely associated with E′ velocity (r = −0.54, p <0.0001), and the area under the receiver operating characteristic curve for QTc as a predictor of DD was 0.82. QTc prolongation was independently associated with reduced E′ velocity (p = 0.021 after adjustment for age, gender, medications, QRS duration, and ejection fraction). In phase 2 of our study QTc was the electrocardiographic parameter most associated with reduced E′ velocity (435 ± 31 vs 419 ± 24 ms; p = 0.004), confirming our phase 1 study findings. In conclusion, QTc prolongation was the electrocardiographic marker most predictive of DD and was independently associated with DD. PMID:21907948

Prolonged QT interval and lipid alterations beyond β-oxidation in very long-chain acyl-CoA dehydrogenase null mouse hearts

PubMed Central

Gélinas, Roselle; Thompson-Legault, Julie; Bouchard, Bertrand; Daneault, Caroline; Mansour, Asmaa; Gillis, Marc-Antoine; Charron, Guy; Gavino, Victor; Labarthe, François

2011-01-01

Patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency frequently present cardiomyopathy and heartbeat disorders. However, the underlying factors, which may be of cardiac or extra cardiac origins, remain to be elucidated. In this study, we tested for metabolic and functional alterations in the heart from 3- and 7-mo-old VLCAD null mice and their littermate counterparts, using validated experimental paradigms, namely, 1) ex vivo perfusion in working mode, with concomitant evaluation of myocardial contractility and metabolic fluxes using 13C-labeled substrates under various conditions; as well as 2) in vivo targeted lipidomics, gene expression analysis as well as electrocardiogram monitoring by telemetry in mice fed various diets. Unexpectedly, when perfused ex vivo, working VLCAD null mouse hearts maintained values similar to those of the controls for functional parameters and for the contribution of exogenous palmitate to β-oxidation (energy production), even at high palmitate concentration (1 mM) and increased energy demand (with 1 μM epinephrine) or after fasting. However, in vivo, these hearts displayed a prolonged rate-corrected QT (QTc) interval under all conditions examined, as well as the following lipid alterations: 1) age- and condition-dependent accumulation of triglycerides, and 2) 20% lower docosahexaenoic acid (an omega-3 polyunsaturated fatty acid) in membrane phospholipids. The latter was independent of liver but affected by feeding a diet enriched in saturated fat (exacerbated) or fish oil (attenuated). Our finding of a longer QTc interval in VLCAD null mice appears to be most relevant given that such condition increases the risk of sudden cardiac death. PMID:21685264

Fine-mapping and initial characterization of QT interval loci in African Americans.

PubMed

Avery, Christy L; Sethupathy, Praveen; Buyske, Steven; He, Qianchuan; Lin, Dan-Yu; Arking, Dan E; Carty, Cara L; Duggan, David; Fesinmeyer, Megan D; Hindorff, Lucia A; Jeff, Janina M; Klein, Liviu; Patton, Kristen K; Peters, Ulrike; Shohet, Ralph V; Sotoodehnia, Nona; Young, Alicia M; Kooperberg, Charles; Haiman, Christopher A; Mohlke, Karen L; Whitsel, Eric A; North, Kari E

2012-01-01

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10(-4)): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10(-5)): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple

Fine-Mapping and Initial Characterization of QT Interval Loci in African Americans

PubMed Central

Avery, Christy L.; Sethupathy, Praveen; Buyske, Steven; He, Qianchuan; Lin, Dan-Yu; Arking, Dan E.; Carty, Cara L.; Duggan, David; Fesinmeyer, Megan D.; Hindorff, Lucia A.; Jeff, Janina M.; Klein, Liviu; Patton, Kristen K.; Peters, Ulrike; Shohet, Ralph V.; Sotoodehnia, Nona; Young, Alicia M.; Kooperberg, Charles; Haiman, Christopher A.; Mohlke, Karen L.; Whitsel, Eric A.; North, Kari E.

2012-01-01

The QT interval (QT) is heritable and its prolongation is a risk factor for ventricular tachyarrhythmias and sudden death. Most genetic studies of QT have examined European ancestral populations; however, the increased genetic diversity in African Americans provides opportunities to narrow association signals and identify population-specific variants. We therefore evaluated 6,670 SNPs spanning eleven previously identified QT loci in 8,644 African American participants from two Population Architecture using Genomics and Epidemiology (PAGE) studies: the Atherosclerosis Risk in Communities study and Women's Health Initiative Clinical Trial. Of the fifteen known independent QT variants at the eleven previously identified loci, six were significantly associated with QT in African American populations (P≤1.20×10−4): ATP1B1, PLN1, KCNQ1, NDRG4, and two NOS1AP independent signals. We also identified three population-specific signals significantly associated with QT in African Americans (P≤1.37×10−5): one at NOS1AP and two at ATP1B1. Linkage disequilibrium (LD) patterns in African Americans assisted in narrowing the region likely to contain the functional variants for several loci. For example, African American LD patterns showed that 0 SNPs were in LD with NOS1AP signal rs12143842, compared with European LD patterns that indicated 87 SNPs, which spanned 114.2 Kb, were in LD with rs12143842. Finally, bioinformatic-based characterization of the nine African American signals pointed to functional candidates located exclusively within non-coding regions, including predicted binding sites for transcription factors such as TBX5, which has been implicated in cardiac structure and conductance. In this detailed evaluation of QT loci, we identified several African Americans SNPs that better define the association with QT and successfully narrowed intervals surrounding established loci. These results demonstrate that the same loci influence variation in QT across multiple

Prolongation of the corrected QT complex--a cause of sudden cardiac death in the mountain environment?

PubMed

Windsor, J S; Rodway, G W; Mukherjee, R; Firth, P G; Shattock, M; Montgomery, H E

2011-03-01

In the mountain environment sudden cardiac death (SCD) has been shown to be responsible for the deaths of up to 52% of downhill skiers and 30% of hikers. The majority of SCD's are precipitated by a ventricular arrhythmia. Although most are likely to result from structural abnormalities associated with conditions such as ischaemic heart disease, a small but significant number may be due to abnormalities in ion channel activity, commonly known as, "channelopathies". Channelopathies have the potential to lengthen the time between ventricular depolarisation and repolarisation that can result in prolongation of the corrected QT interval (QTc) and episodes of polymorphic ventricular tachycardia (PVT) and eventually, ventricular fibrillation. This review examines the factors that prolong the QTc interval in the mountain environment and outlines a practical framework for preventing the life threatening arrhythmias that are associated with this condition.

Automated measurements for individualized heart rate correction of the QT interval.

PubMed

Mason, Jay W; Moon, Thomas E

2015-04-01

Subject-specific electrocardiographic QT interval correction for heart rate is often used in clinical trials with frequent electrocardiographic recordings. However, in these studies relatively few 10-s, 12-lead electrocardiograms may be available for calculating the individual correction. Highly automated QT and RR measurement tools have made it practical to measure electrocardiographic intervals on large volumes of continuous electrocardiogram data. The purpose of this study was to determine whether an automated method can be used in lieu of a manual method. In 49 subjects who completed all treatments in a four-armed crossover study we compared two methods for derivation of individualized rate-correction coefficients: manual measurement on 10-s electrocardiograms and automated measurement of QT and RR during continuous 24-h electrocardiogram recordings. The four treatments, received by each subject in a latin-square randomization sequence were placebo, moxifloxacin, and two doses of an investigational drug. Analysis of continuous electrocardiogram data yielded a lower standard deviation of QT:RR regression values than the manual method, though the differences were not statistically significant. The within-subject and within-treatment coefficients of variation between the manual and automated methods were not significantly different. Corrected QT values from the two methods had similar rates of true and false positive identification of moxifloxacin's QT prolonging effect. An automated method for individualized rate correction applied to continuous electrocardiogram data could be advantageous in clinical trials, as the automated method is simpler, is based upon a much larger volume of data, yields similar results, and requires no human over-reading of the measurements. © The Author(s) 2015.

Randomized, blinded, placebo- and positive-controlled crossover study to determine the effect of multiple doses of apixaban on the QTc interval.

PubMed

Frost, Charles; Nepal, Sunil; Byon, Wonkyung; Moore, Kenneth; Reeves, Richard A; Boyd, Rebecca; LaCreta, Frank

2015-05-01

Apixaban is an oral, direct factor Xa inhibitor indicated for the prevention and treatment of thromboembolic disease. This randomized, blinded, 4-way crossover study investigated the potential effect of apixaban on the QTc interval. Forty healthy subjects (39 completers) each received 3 days of the following treatments: blinded apixaban 10 mg once daily (QD), 50 mg QD (supratherapeutic), matched apixaban placebo QD, and a single dose of open-label moxifloxacin 400 mg on Day 3, preceded by 2 days of placebo QD. Triplicate electrocardiograms obtained over 24 hours on Days -1 (baseline) and 3 were read by a blinded third party. The mean placebo-adjusted, time-matched, Fridericia-corrected change from baseline QTc (ΔΔQTcF) for apixaban and moxifloxacin was estimated at each time point. The maximum ΔΔQTcF was 1.51 milliseconds (one-sided upper 95% confidence interval [CI] 3.71 milliseconds) after apixaban 50 mg QD, 1.36 milliseconds (one-sided upper 95%CI 3.54 milliseconds) after apixaban 10 mg QD, and 10.21 milliseconds (lower 95%CI 8.07 milliseconds) after moxifloxacin. Concentration-response analysis suggested no evidence of a positive relationship between apixaban concentration and ΔQTcF. Apixaban doses up to 50 mg QD for 3 days were well tolerated and did not prolong the QTc interval in healthy subjects. © 2015, The American College of Clinical Pharmacology.

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with ankylosing spondylitis.

PubMed

Acar, Gurkan; Yorgun, Hikmet; Inci, Mehmet Fatih; Akkoyun, Murat; Bakan, Betul; Nacar, Alper Bugra; Dirnak, Imran; Cetin, Gozde Yildirim; Bozoglan, Orhan

2013-04-12

OBJECTIVES: Ankylosing spondylitis (AS) is a chronic multi-systemic inflammatory rheumatic disorder. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using Tp-e interval and Tp-e/QT ratio in patients with AS, and to assess the relation with inflammation. METHODS: Sixty-two patients with AS and 50 controls were included. Tp-e interval and Tp-e/QT ratio were measured from a 12-lead electrocardiogram, and the Tp-e interval corrected for heart rate. The plasma level of high sensitive C-reactive protein (hsCRP) was measured. These parameters were compared between groups. RESULTS: In electrocardiographic parameters analysis, QT dispersion (QTd) and corrected QTd were significantly increased in AS patients compared to the controls (31.7 ± 9.6 vs 28.2 ± 7.4 and 35.8 ± 11.5 vs 30.6 ± 7.9 ms, P = 0.03 and P = 0.007, respectively). cTp-e interval and Tp-e/QT ratio were also significantly higher in AS patients (92.1 ± 10.2 vs 75.8 ± 8.4 and 0.22 ± 0.02 vs 0.19 ± 0.02 ms, all P values <0.001). cTp-e interval and Tp-e/QT ratio were significantly correlated with hsCRP (r = 0.63, P < 0.001 and r = 0.49, P < 0.001, respectively). CONCLUSIONS: Our study revealed that Tp-e interval and Tp-e/QT ratio were increased in AS patients. These electrocardiographic ventricular repolarization indexes were significantly correlated with the plasma level of hsCRP.

Multiple Independent Genetic Factors at NOS1AP Modulate the QT Interval in a Multi-Ethnic Population

PubMed Central

Arking, Dan E.; Khera, Amit; Xing, Chao; Kao, W. H. Linda; Post, Wendy; Boerwinkle, Eric; Chakravarti, Aravinda

2009-01-01

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6×10−5) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP × sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63×10−8), as well as the sex-interaction with rs16847548 (P = 8.68×10−6). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval. PMID:19180230

Co-Prescription of QT-Interval Prolonging Drugs: An Analysis in a Large Cohort of Geriatric Patients

PubMed Central

Schächtele, Simone; Tümena, Thomas; Gaßmann, Karl-Günter; Fromm, Martin F.; Maas, Renke

2016-01-01

Background Drug-induced QT-interval prolongation is associated with occurrence of potentially fatal Torsades de Pointes arrhythmias (TdP). So far, data regarding the overall burden of QT-interval prolonging drugs (QT-drugs) in geriatric patients are limited. Objective This study was performed to assess the individual burden of QT-interval prolonging drugs (QT-drugs) in geriatric polymedicated patients and to identify the most frequent and risky combinations of QT-drugs. Methods In the discharge medication of geriatric patients between July 2009 and June 2013 from the Geriatrics in Bavaria–Database (GiB-DAT) (co)-prescriptions of QT-drugs were investigated. QT-drugs were classified according to a publicly available reference site (CredibleMeds®) as ALL-QT-drugs (associated with any QT-risk) or High-risk-QT-drugs (corresponding to QT-drugs with known risk of Torsades de Pointes according to CredibleMeds®) and in addition as SmPC-high-risk-QT-drugs (according to the German prescribing information (SmPC) contraindicated co-prescription with other QT-drugs). Results Of a cohort of 130,434 geriatric patients (mean age 81 years, 67% women), prescribed a median of 8 drugs, 76,594 patients (58.7%) received at least one ALL-QT-drug. Co-prescriptions of two or more ALL-QT-drugs were observed in 28,768 (22.1%) patients. Particularly risky co-prescriptions of High-risk-QT-drugs or SmPC-high-risk-QT-drugs with at least on further QT-drug occurred in 55.9% (N = 12,633) and 54.2% (N = 12,429) of these patients, respectively. Consideration of SmPCs (SmPC-high-risk-QT-drugs) allowed the identification of an additional 15% (N = 3,999) patients taking a risky combination that was not covered by the commonly used CredibleMeds® classification. Only 20 drug-drug combinations accounted for more than 90% of these potentially most dangerous co-prescriptions. Conclusion In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT

Co-Prescription of QT-Interval Prolonging Drugs: An Analysis in a Large Cohort of Geriatric Patients.

PubMed

Schächtele, Simone; Tümena, Thomas; Gaßmann, Karl-Günter; Fromm, Martin F; Maas, Renke

2016-01-01

Drug-induced QT-interval prolongation is associated with occurrence of potentially fatal Torsades de Pointes arrhythmias (TdP). So far, data regarding the overall burden of QT-interval prolonging drugs (QT-drugs) in geriatric patients are limited. This study was performed to assess the individual burden of QT-interval prolonging drugs (QT-drugs) in geriatric polymedicated patients and to identify the most frequent and risky combinations of QT-drugs. In the discharge medication of geriatric patients between July 2009 and June 2013 from the Geriatrics in Bavaria-Database (GiB-DAT) (co)-prescriptions of QT-drugs were investigated. QT-drugs were classified according to a publicly available reference site (CredibleMeds®) as ALL-QT-drugs (associated with any QT-risk) or High-risk-QT-drugs (corresponding to QT-drugs with known risk of Torsades de Pointes according to CredibleMeds®) and in addition as SmPC-high-risk-QT-drugs (according to the German prescribing information (SmPC) contraindicated co-prescription with other QT-drugs). Of a cohort of 130,434 geriatric patients (mean age 81 years, 67% women), prescribed a median of 8 drugs, 76,594 patients (58.7%) received at least one ALL-QT-drug. Co-prescriptions of two or more ALL-QT-drugs were observed in 28,768 (22.1%) patients. Particularly risky co-prescriptions of High-risk-QT-drugs or SmPC-high-risk-QT-drugs with at least on further QT-drug occurred in 55.9% (N = 12,633) and 54.2% (N = 12,429) of these patients, respectively. Consideration of SmPCs (SmPC-high-risk-QT-drugs) allowed the identification of an additional 15% (N = 3,999) patients taking a risky combination that was not covered by the commonly used CredibleMeds® classification. Only 20 drug-drug combinations accounted for more than 90% of these potentially most dangerous co-prescriptions. In a geriatric study population co-prescriptions of two and more QT-drugs were common. A considerable proportion of QT-drugs with higher risk only could be detected by

The analysis of QT interval and repolarization morphology of the heart in chronic exposure to lead.

PubMed

Kiełtucki, J; Dobrakowski, M; Pawlas, N; Średniawa, B; Boroń, M; Kasperczyk, S

2017-10-01

There are no common recommendations regarding electrocardiographic monitoring in occupationally exposed workers. Therefore, the present study was designed to investigate whether exposure to lead results in an increase of selected electrocardiography (ECG) pathologies, such as QT interval prolongation and repolarization disorders, in occupationally exposed workers. The study group included 180 workers occupationally exposed to lead compounds. The exposed group was divided according to the median of the mean blood lead level (PbB mean ) calculated based on a series of measurements performed during 5-year observation period (35 µg/dl) into two subgroups: low exposure (LE, PbB mean = 20.0-35.0 µg/dl) and high exposure (HE, PbB mean = 35.1-46.4 µg/dl). The control group consisted of 69 healthy workers without occupational exposure to lead. ECG evaluation included the analysis of heart rate (HR), QT interval and repolarization abnormalities. Mean QT interval was significantly greater in the exposed population than in the control group by 2%. In the HE group, mean QT interval was significantly greater than in the control group by 4% and significantly different from those noted in the LE group. Positive correlations between QT interval and lead exposure indices were also reported. Besides, there was a negative correlation between HR and blood lead level. Increased concentration of lead in the blood above 35 μg/dl is associated with the QT interval prolongation, which may trigger arrhythmias when combined with other abnormalities, such as long QT syndrome. Therefore, electrocardiographic evaluation should be a part of a routine monitoring of occupationally exposed populations.

Increased Short-Term Variability of the QT Interval in Professional Soccer Players: Possible Implications for Arrhythmia Prediction

PubMed Central

Lengyel, Csaba; Orosz, Andrea; Hegyi, Péter; Komka, Zsolt; Udvardy, Anna; Bosnyák, Edit; Trájer, Emese; Pavlik, Gábor; Tóth, Miklós; Wittmann, Tibor; Papp, Julius Gy.; Varró, András; Baczkó, István

2011-01-01

Background Sudden cardiac death in competitive athletes is rare but it is significantly more frequent than in the normal population. The exact cause is seldom established and is mostly attributed to ventricular fibrillation. Myocardial hypertrophy and slow heart rate, both characteristic changes in top athletes in response to physical conditioning, could be associated with increased propensity for ventricular arrhythmias. We investigated conventional ECG parameters and temporal short-term beat-to-beat variability of repolarization (STVQT), a presumptive novel parameter for arrhythmia prediction, in professional soccer players. Methods Five-minute 12-lead electrocardiograms were recorded from professional soccer players (n = 76, all males, age 22.0±0.61 years) and age-matched healthy volunteers who do not participate in competitive sports (n = 76, all males, age 22.0±0.54 years). The ECGs were digitized and evaluated off-line. The temporal instability of beat-to-beat heart rate and repolarization were characterized by the calculation of short-term variability of the RR and QT intervals. Results Heart rate was significantly lower in professional soccer players at rest (61±1.2 vs. 72±1.5/min in controls). The QT interval was prolonged in players at rest (419±3.1 vs. 390±3.6 in controls, p<0.001). QTc was significantly longer in players compared to controls calculated with Fridericia and Hodges correction formulas. Importantly, STVQT was significantly higher in players both at rest and immediately after the game compared to controls (4.8±0.14 and 4.3±0.14 vs. 3.5±0.10 ms, both p<0.001, respectively). Conclusions STVQT is significantly higher in professional soccer players compared to age-matched controls, however, further studies are needed to relate this finding to increased arrhythmia propensity in this population. PMID:21526208

Coffee, alcohol, smoking, physical activity and QT interval duration: results from the Third National Health and Nutrition Examination Survey.

PubMed

Zhang, Yiyi; Post, Wendy S; Dalal, Darshan; Blasco-Colmenares, Elena; Tomaselli, Gordon F; Guallar, Eliseo

2011-02-28

Abnormalities in the electrocardiographic QT interval duration have been associated with an increased risk of ventricular arrhythmias and sudden cardiac death. However, there is substantial uncertainty about the effect of modifiable factors such as coffee intake, cigarette smoking, alcohol consumption, and physical activity on QT interval duration. We studied 7795 men and women from the Third National Health and Nutrition Survey (NHANES III, 1988-1994). Baseline QT interval was measured from the standard 12-lead electrocardiogram. Coffee and tea intake, alcohol consumption, leisure-time physical activities over the past month, and lifetime smoking habits were determined using validated questionnaires during the home interview. In the fully adjusted model, the average differences in QT interval comparing participants drinking ≥6 cups/day to those who did not drink any were -1.2 ms (95% CI -4.4 to 2.0) for coffee, and -2.0 ms (-11.2 to 7.3) for tea, respectively. The average differences in QT interval duration comparing current to never smokers was 1.2 ms (-0.6 to 2.9) while the average difference in QT interval duration comparing participants drinking ≥7 drinks/week to non-drinkers was 1.8 ms (-0.5 to 4.0). The age, race/ethnicity, and RR-interval adjusted differences in average QT interval duration comparing men with binge drinking episodes to non-drinkers or drinkers without binge drinking were 2.8 ms (0.4 to 5.3) and 4.0 ms (1.6 to 6.4), respectively. The corresponding differences in women were 1.1 (-2.9 to 5.2) and 1.7 ms (-2.3 to 5.7). Finally, the average differences in QT interval comparing the highest vs. the lowest categories of total physical activity was -0.8 ms (-3.0 to 1.4). Binge drinking was associated with longer QT interval in men but not in women. QT interval duration was not associated with other modifiable factors including coffee and tea intake, smoking, and physical activity.

Impact of ancestry and common genetic variants on QT interval in African Americans.

PubMed

Smith, J Gustav; Avery, Christy L; Evans, Daniel S; Nalls, Michael A; Meng, Yan A; Smith, Erin N; Palmer, Cameron; Tanaka, Toshiko; Mehra, Reena; Butler, Anne M; Young, Taylor; Buxbaum, Sarah G; Kerr, Kathleen F; Berenson, Gerald S; Schnabel, Renate B; Li, Guo; Ellinor, Patrick T; Magnani, Jared W; Chen, Wei; Bis, Joshua C; Curb, J David; Hsueh, Wen-Chi; Rotter, Jerome I; Liu, Yongmei; Newman, Anne B; Limacher, Marian C; North, Kari E; Reiner, Alexander P; Quibrera, P Miguel; Schork, Nicholas J; Singleton, Andrew B; Psaty, Bruce M; Soliman, Elsayed Z; Solomon, Allen J; Srinivasan, Sathanur R; Alonso, Alvaro; Wallace, Robert; Redline, Susan; Zhang, Zhu-Ming; Post, Wendy S; Zonderman, Alan B; Taylor, Herman A; Murray, Sarah S; Ferrucci, Luigi; Arking, Dan E; Evans, Michele K; Fox, Ervin R; Sotoodehnia, Nona; Heckbert, Susan R; Whitsel, Eric A; Newton-Cheh, Christopher

2012-12-01

Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12,097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13,105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5 × 10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2 × 10(-15)) and ATP1B1 (rs1320976, P=2 × 10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN. We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of African ancestry.

The genetics underlying acquired long QT syndrome: impact for genetic screening.

PubMed

Itoh, Hideki; Crotti, Lia; Aiba, Takeshi; Spazzolini, Carla; Denjoy, Isabelle; Fressart, Véronique; Hayashi, Kenshi; Nakajima, Tadashi; Ohno, Seiko; Makiyama, Takeru; Wu, Jie; Hasegawa, Kanae; Mastantuono, Elisa; Dagradi, Federica; Pedrazzini, Matteo; Yamagishi, Masakazu; Berthet, Myriam; Murakami, Yoshitaka; Shimizu, Wataru; Guicheney, Pascale; Schwartz, Peter J; Horie, Minoru

2016-05-07

Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors. We screened for the five major LQTS genes among 188 aLQTS probands (55 ± 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 ± 39 ms, shorter than in cLQTS (478 ± 46 ms, P < 0.001) and longer than in non-carriers (406 ± 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7-41%] vs. 64% [95% CI 43-82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations. A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.

Dispersion durations of P-wave and QT interval in children treated with a ketogenic diet.

PubMed

Doksöz, Önder; Güzel, Orkide; Yılmaz, Ünsal; Işgüder, Rana; Çeleğen, Kübra; Meşe, Timur

2014-04-01

Limited data are available on the effects of a ketogenic diet on dispersion duration of P-wave and QT-interval measures in children. We searched for the changes in these measures with serial electrocardiograms in patients treated with a ketogenic diet. Twenty-five drug-resistant patients with epilepsy treated with a ketogenic diet were enrolled in this study. Electrocardiography was performed in all patients before the beginning and at the sixth month after implementation of the ketogenic diet. Heart rate, maximum and minimum P-wave duration, P-wave dispersion, and maximum and minimum corrected QT interval and QT dispersion were manually measured from the 12-lead surface electrocardiogram. Minimum and maximum corrected QT and QT dispersion measurements showed nonsignificant increase at month 6 compared with baseline values. Other previously mentioned electrocardiogram parameters also showed no significant changes. A ketogenic diet of 6 months' duration has no significant effect on electrocardiogram parameters in children. Further studies with larger samples and longer duration of follow-up are needed to clarify the effects of ketogenic diet on P-wave dispersion and corrected QT and QT dispersion. Copyright © 2014 Elsevier Inc. All rights reserved.

Coffee, Alcohol, Smoking, Physical Activity and QT Interval Duration: Results from the Third National Health and Nutrition Examination Survey

PubMed Central

Zhang, Yiyi; Post, Wendy S.; Dalal, Darshan; Blasco-Colmenares, Elena; Tomaselli, Gordon F.; Guallar, Eliseo

2011-01-01

Background Abnormalities in the electrocardiographic QT interval duration have been associated with an increased risk of ventricular arrhythmias and sudden cardiac death. However, there is substantial uncertainty about the effect of modifiable factors such as coffee intake, cigarette smoking, alcohol consumption, and physical activity on QT interval duration. Methods We studied 7795 men and women from the Third National Health and Nutrition Survey (NHANES III, 1988–1994). Baseline QT interval was measured from the standard 12-lead electrocardiogram. Coffee and tea intake, alcohol consumption, leisure-time physical activities over the past month, and lifetime smoking habits were determined using validated questionnaires during the home interview. Results In the fully adjusted model, the average differences in QT interval comparing participants drinking ≥6 cups/day to those who did not drink any were −1.2 ms (95% CI −4.4 to 2.0) for coffee, and −2.0 ms (−11.2 to 7.3) for tea, respectively. The average differences in QT interval duration comparing current to never smokers was 1.2 ms (−0.6 to 2.9) while the average difference in QT interval duration comparing participants drinking ≥7 drinks/week to non-drinkers was 1.8 ms (−0.5 to 4.0). The age, race/ethnicity, and RR-interval adjusted differences in average QT interval duration comparing men with binge drinking episodes to non-drinkers or drinkers without binge drinking were 2.8 ms (0.4 to 5.3) and 4.0 ms (1.6 to 6.4), respectively. The corresponding differences in women were 1.1 (−2.9 to 5.2) and 1.7 ms (−2.3 to 5.7). Finally, the average differences in QT interval comparing the highest vs. the lowest categories of total physical activity was −0.8 ms (−3.0 to 1.4). Conclusion Binge drinking was associated with longer QT interval in men but not in women. QT interval duration was not associated with other modifiable factors including coffee and tea intake, smoking, and physical activity. PMID

Possible interethnic differences in quinidine-induced QT prolongation between healthy Caucasian and Korean subjects

PubMed Central

Shin, Jae-Gook; Kang, Won-ku; Shon, Ji-Hong; Arefayene, Million; Yoon, Young-Ran; Kim, Kyung-Ah; Kim, Doo-Il; Kim, Dong-Soo; Cho, Kwang-Hyun; Woosley, Raymond L; Flockhart, David A

2007-01-01

Aims The aim of this study was to evaluate the pharmacokinetics and pharmacodynamics of quinidine-induced QT prolongation in healthy Caucasian and Korean subjects to investigate interethnic differences in susceptibility to drug-induced arrhythmia. Methods A randomized, double-blind crossover study was conducted in 24 (12 male and 12 female) Korean and 13 (seven male and six female) Caucasian subjects. After a 20 min infusion of quinidine (4 mg kg−1) or saline, the serum concentration of quinidine and the QT interval corrected by Bazett's formula (QTc) were monitored. The dynamic data were analyzed by means of a population modelling approach using NONMEM. Results There were no statistical differences in the pharmacokinetic profiles of quinidine between ethnic groups. The QTc values in Caucasians were higher than those in Koreans at the same quinidine concentrations, especially at higher quinidine concentrations and in female subjects. According to an Emax model , the population modelling approach revealed that E0 (ms) was related to gender (408 + [34*(1 − Sex)]; 1 for male and 0 for female), ΔEmax (ms) was related to ethnicity ((136*fETHN) + Cfemale: fETHN = 1 for Koreans and 1.26 for Caucasians; Cfemale was 106 only for Caucasian females), and EC50 was estimated to be 3.13 µm. Conclusions These results suggest that Korean subjects were less sensitive to quinidine-induced QT prolongation than Caucasian subjects, and that this trend was particularly true for females. Further population-based studies are merited to characterize more completely the ethnic differences in drug-induced QT prolongation between Asians and other ethnic groups. PMID:17096683

KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1

PubMed Central

Kapplinger, Jamie D; Erickson, Anders; Asuri, Sirisha; Tester, David J; McIntosh, Sarah; Kerr, Charles R; Morrison, Julie; Tang, Anthony; Sanatani, Shubhayan; Arbour, Laura; Ackerman, Michael J

2017-01-01

Background Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. Methods 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. Results For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. Conclusions Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants. PMID:28264985

Relationship of QT dispersion with sex hormones and insulin in young women with polycystic ovary syndrome: an observational study.

PubMed

Gazi, Emine; Gencer, Meryem; Hancı, Volkan; Temiz, Ahmet; Altun, Burak; Cakır Güngör, Ayşe Nur; Oztürk, Ufuk; Kırılmaz, Bahadır

2013-12-01

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in reproductive women. Cardiovascular disease risk factors are more frequent in this population. We aimed in this study to investigate presence of QT dispersion and effects of sex hormones and insulin on QT duration in young PCOS patients. This present study was cross-sectional observational study. A total of 47 women, 25 patients with PCOS and 22 healthy, were included. Serum testosterone, estradiol and insulin levels were studied and electrocardiography was performed at 2nd or 3th days of menstrual cycle. The study population was divided into groups according to serum testosterone and estradiol levels. Sub-groups and pairwise groups were compared by Mann-Whitney U or student t-test. The associations of QTc durations with hormone levels were calculated using Spearman rank correlation analysis. The results were evaluated at the p<0.05 significance level. No differences found between groups regarding to demographic parameters. Estradiol and testosterone levels were higher in patients with PCOS (41.12 ± 13.59 vs. 35.57 ± 19.29 pg/mL, p=0.09 and 105 ± 58.5 vs. 17.6 ± 10.9 ng/dL, p=0.01, respectively). QT dispersion was significantly longer in PCOS patients (47.1 vs. 32.7 ms, p=0.01). A positive correlation was found between the serum insulin level and QTc min, QTc max, and QTc mean (r=0.402, p=0.011; r=0.341, p=0.033; r=0.337, p=0.036; respectively). QT dispersion with serum testosterone and estradiol levels were positively correlated (r=0.525, p=0.001 and r=0.326, p=0.046; respectively). Our results suggest that QT dispersion is prolonged and testosterone, estradiol and insulin are associated with QT duration in young PCOS patients.

The Impact of Ancestry and Common Genetic Variants on QT Interval in African Americans

PubMed Central

Smith, J. Gustav; Avery, Christy L.; Evans, Daniel S.; Nalls, Michael A.; Meng, Yan A.; Smith, Erin N.; Palmer, Cameron; Tanaka, Toshiko; Mehra, Reena; Butler, Anne M.; Young, Taylor; Buxbaum, Sarah G.; Kerr, Kathleen F.; Berenson, Gerald S.; Schnabel, Renate B.; Li, Guo; Ellinor, Patrick T.; Magnani, Jared W.; Chen, Wei; Bis, Joshua C.; Curb, J. David; Hsueh, Wen-Chi; Rotter, Jerome I.; Liu, Yongmei; Newman, Anne B.; Limacher, Marian C.; North, Kari E.; Reiner, Alexander P.; Quibrera, P. Miguel; Schork, Nicholas J.; Singleton, Andrew B.; Psaty, Bruce M.; Soliman, Elsayed Z.; Solomon, Allen J.; Srinivasan, Sathanur R.; Alonso, Alvaro; Wallace, Robert; Redline, Susan; Zhang, Zhu-Ming; Post, Wendy S.; Zonderman, Alan B.; Taylor, Herman A.; Murray, Sarah S.; Ferrucci, Luigi; Arking, Dan E.; Evans, Michele K.; Fox, Ervin R.; Sotoodehnia, Nona; Heckbert, Susan R.; Whitsel, Eric A.; Newton-Cheh, Christopher

2013-01-01

Background Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death (SCD) and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. Methods and Results First, individual estimates of African and European ancestry were inferred from genome-wide single nucleotide polymorphism (SNP) data in seven population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from electrocardiograms. Second, imputation was performed for 2.8 million SNPs and a genome-wide association (GWA) study of QT interval performed in ten cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval (p=0.94). Genome-wide significant associations (p<2.5×10−8) were identified with SNPs at two loci, upstream of the genes NOS1AP (rs12143842, p=2×10−15) and ATP1B1 (rs1320976, p=2×10−10). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low p-values (p<10−5) were observed for SNPs at several other loci previously identified in GWA studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF and PLN. Conclusions We observed no difference in duration of cardiac repolarization with global genetic indices of African ancestry. In addition, our GWA study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include African Americans. PMID:23166209

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with non-dipper hypertension.

PubMed

Demir, Mehmet; Uyan, Umut

2014-01-01

Non-dipper hypertension is associated with increased cardiovascular morbidity and mortality. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using Tp-e interval and Tp-e/QT ratio in patients with non-dipper hypertension. This study included 80 hypertensive patients. Hypertensive patients were divided into two groups: 50 dipper patients (29 male, mean age 51.5 ± 8 years) and 30 non-dipper patients (17 male, mean age 50.6 ± 5.4 years). Tp-e interval and Tp-e/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared between groups. No statistically significant difference was found between two groups in terms of basic characteristics. In electrocardiographic parameters analysis, QT dispersion (QTd) and corrected QTd were significantly increased in non-dipper patients compared to the dippers (39.4 ± 11.5 versus 27.3 ± 7.5 ms and 37.5 ± 9.5 versus 29.2 ± 6.5 ms, p = 0.001 and p = 0.01, respectively). Tp-e interval and Tp-e/QT ratio were also significantly higher in non-dipper patients (97.5 ± 11.2 versus 84.2 ± 8.3 ms and 0.23 ± 0.02 versus 0.17 ± 0.02, all p value <0.001). Our study revealed that QTd, Tp-e interval and Tp-e/QT ratio are prolonged in patients with non-dipper hypertension.

Preclinical QT safety assessment: cross-species comparisons and human translation from an industry consortium.

PubMed

Holzgrefe, Henry; Ferber, Georg; Champeroux, Pascal; Gill, Michael; Honda, Masaki; Greiter-Wilke, Andrea; Baird, Theodore; Meyer, Olivier; Saulnier, Muriel

2014-01-01

In vivo models have been required to demonstrate relative cardiac safety, but model sensitivity has not been systematically investigated. Cross-species and human translation of repolarization delay, assessed as QT/QTc prolongation, has not been compared employing common methodologies across multiple species and sites. Therefore, the accurate translation of repolarization results within and between preclinical species, and to man, remains problematic. Six pharmaceutical companies entered into an informal consortium designed to collect high-resolution telemetered data in multiple species (dog; n=34, cynomolgus; n=37, minipig; n=12, marmoset; n=14, guinea pig; n=5, and man; n=57). All animals received vehicle and varying doses of moxifloxacin (3-100 mg/kg, p.o.) with telemetered ECGs (≥500 Hz) obtained for 20-24h post-dose. Individual probabilistic QT-RR relationships were derived for each subject. The rate-correction efficacies of the individual (QTca) and generic correction formulae (Bazett, Fridericia, and Van de Water) were objectively assessed as the mean squared slopes of the QTc-RR relationships. Normalized moxifloxacin QTca responses (Veh Δ%/μM) were derived for 1h centered on the moxifloxacin Tmax. All QT-RR ranges demonstrated probabilistic uncertainty; slopes varied distinctly by species where dog and human exhibited the lowest QT rate-dependence, which was much steeper in the cynomolgus and guinea pig. Incorporating probabilistic uncertainty, the normalized QTca-moxifloxacin responses were similarly conserved across all species, including man. The current results provide the first unambiguous evidence that all preclinical in vivo repolarization assays, when accurately modeled and evaluated, yield results that are consistent with the conservation of moxifloxacin-induced QT prolongation across all common preclinical species. Furthermore, these outcomes are directly transferable across all species including man. The consortium results indicate that the

Cardiovascular Effects of Energy Drinks in Familial Long QT Syndrome: A Randomized Cross-Over Study.

PubMed

Gray, Belinda; Ingles, Jodie; Medi, Caroline; Driscoll, Timothy; Semsarian, Christopher

2017-03-15

Caffeinated energy drinks may trigger serious cardiac effects. The aim of this study was to determine the cardiovascular effects of caffeinated energy drink consumption in patients with familial long QT syndrome (LQTS). From 2014-2016, 24 LQTS patients aged 16-50 years were recruited to a randomized, double-blind, cross-over study of energy drink (ED) versus control (CD) with participants acting as their own controls (one week washout). The primary study outcome was an increase in corrected QT interval (QTc) by >20ms. Secondary outcomes were changes in systolic and diastolic blood pressure. In 24 patients with LQTS (no dropout), mean age was 29±9 years, 13/24 (54%) were female, and 8/24 (33%) were probands. Intention to treat analysis revealed no significant change in QTc with ED compared with CD (12±28ms vs 16±27ms, 3% vs 4%, p=0.71). The systolic and diastolic blood pressure significantly increased with ED compared to CD (peak change 7±16mmHg vs 1±16mmHg, 6% vs 0.8%, p=0.046 and 8±10 vs 2±9mmHg, 11% vs 3% p=0.01 respectively). These changes correlated with significant increases in serum caffeine (14.6±11.3 vs 0.5±0.1μmol/L, p<0.001) and serum taurine (737±199 vs -59±22μmol/L, p<0.001). There were three patients with dangerous QTc prolongation of ≥50ms following energy drink consumption. Caffeinated energy drinks have significant haemodynamic effects in patients with LQTS, especifically an acute increase in blood pressure. Since dangerous QTc prolongation was seen in some LQTS patients, we recommend caution in young patients with LQTS consuming energy drinks. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Evaluation of Tp-e interval and Tp-e/QT ratio in patients with rheumatoid arthritis.

PubMed

Acar, Gu Rkan; Akkoyun, Murat; Nacar, Alper Bugra; Dirnak, Imran; Yıldırım Çetin, Gözde; Nur Yıldırım, Makbule; Zencir, Cemil; Karaman, Kayıhan; Cetin, Mustafa; Sayarlıoğlu, Mehmet

2014-01-01

Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using the Tp-e interval and Tp-e/QT ratio in patients with rheumatoid arthritis (RA), and to assess the relation with inflammation. Ninety-six patients (72 females, 24 males; mean age 43.8±11.8 years) with RA and 50 controls (35 females, 15 males; mean age 44.2±11.1 years) were included. From the 12-lead electrocardiogram, Tp-e interval and Tp-e/QT ratio were measured. Blood samples were taken for erythrocyte sedimentation rate (ESR) and plasma levels of C-reactive protein (CRP). These parameters were compared between groups. The relationship between ventricular repolarization and inflammation was assessed by Pearson correlation coefficients. Tp-e interval and Tp-e/QT ratio were increased in RA patients compared to the controls (72.6±8.2 vs 66.4±8.5 ms, 0.20±0.02 vs 0.18±0.02; p<0.001 and p<0.001, respectively). The Tp-e interval was significantly correlated with CRP, ESR, and disease activity score (DAS-28) (r=0.56, p<0.001, r=0.57, p<0.001, and r=0.29, p=0.02, respectively). The Tp-e/QT ratio was also correlated with CRP, ESR, and DAS-28 score (r=0.43, p<0.001, r=0.53, p<0.001, and r=0.25, p=0.03, respectively). In RA patients, the increased frequency of ventricular arrhythmias may be explained by increased indexes of ventricular repolarization and their relationship with inflammation.

Population Pharmacokinetic-Pharmacodynamic Analysis to Compare the Effect of Moxifloxacin on QT Interval Prolongation Between Healthy Korean and Japanese Subjects.

PubMed

Choi, Hyang-Ki; Jung, Jin Ah; Fujita, Tomoe; Amano, Hideki; Ghim, Jong-Lyul; Lee, Dong-Hwan; Tabata, Kenichi; Song, Il-Dae; Maeda, Mika; Kumagai, Yuji; Mendzelevski, Boaz; Shin, Jae-Gook

2016-12-01

The goal of this study was to evaluate the moxifloxacin-induced QT interval prolongation in healthy male and female Korean and Japanese volunteers to investigate interethnic differences. This multicenter, randomized, double-blind, placebo-controlled, 2-way crossover study was conducted in healthy male and female Korean and Japanese volunteers. In each period, a single dose of moxifloxacin or placebo 400 mg was administered orally under fasting conditions. Triplicate 12-lead ECGs were recorded at defined time points before, up to 24 hours after dosing, and at corresponding time points during baseline. Serial blood sampling was conducted for pharmacokinetic analysis of moxifloxacin. The pharmacokinetic-pharmacodynamic data between the 2 ethnic groups were compared by using a typical analysis based on the intersection-union test and a nonlinear mixed effects method. A total of 39 healthy subjects (Korean, male: 10, female: 10; Japanese, male: 10, female: 9) were included in the analysis. The concentration-effect analysis revealed that there was no change in slope (and confirmed that the difference was caused by a change in the pharmacokinetic model of moxifloxacin). A 2-compartment model with first-order absorption provided the best description of moxifloxacin's pharmacokinetic parameters. Weight and sex were selected as significant covariates for central volume of distribution and intercompartmental clearance, respectively. An E max model (E[C]=[E max ⋅C]/[EC 50 +C]) described the QT interval data of this study well. However, ethnicity was not found to be a significant factor in a pharmacokinetic-pharmacodynamic link model. The drug-induced QTc prolongations evaluated using moxifloxacin as the probe did not seem to be significantly different between these Korean and Japanese subjects. ClinicalTrials.gov identifier: NCT01876316. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

PK/PD Modelling of the QT Interval: a Step Towards Defining the Translational Relationship Between In Vitro, Awake Beagle Dogs, and Humans.

PubMed

Marostica, Eleonora; Van Ammel, Karel; Teisman, Ard; Gallacher, David; Van Bocxlaer, Jan; De Ridder, Filip; Boussery, Koen; Vermeulen, An

2016-07-01

Inhibiting the human ether-a-go-go-related gene (hERG)-encoded potassium ion channel is positively correlated with QT-interval prolongation in vivo, which is considered a risk factor for the occurrence of Torsades de Pointes (TdP). A pharmacokinetic/pharmacodynamic model was developed for four compounds that reached the clinic, to relate drug-induced QT-interval change in awake dogs and humans and to derive a translational scaling factor a 1. Overall, dogs were more sensitive than humans to QT-interval change, an a 1 of 1.5 was found, and a 10% current inhibition in vitro produced a higher percent QT-interval change in dogs as compared to humans. The QT-interval changes in dogs were predictive for humans. In vitro and in vivo information could reliably describe the effects in humans. Robust translational knowledge is likely to reduce the need for expensive thorough QT studies; therefore, expanding this work to more compounds is recommended.

Heterogeneous Phenotype of Long QT Syndrome Caused by the KCNH2-H562R Mutation: Importance of Familial Genetic Testing.

PubMed

Muñoz-Esparza, Carmen; García-Molina, Esperanza; Salar-Alcaraz, Mariela; Peñafiel-Verdú, Pablo; Sánchez-Muñoz, Juan J; Martínez Sánchez, Juan; Cabañas-Perianes, Valentín; Valdés Chávarri, Mariano; García Alberola, Arcadio; Gimeno-Blanes, Juan R

2015-10-01

Long QT syndrome is an inherited ion channelopathy that leads to syncope and sudden death. Because of the heterogeneous phenotype of this disease, genetic testing is fundamental to detect individuals with concealed long QT syndrome. In this study, we determined the features of a family with 13 carriers of the KCNH2-H562R missense mutation, which affects the pore region of the HERG channel. We identified the KCNH2-H562R mutation in a 65-year-old man with a prolonged QTc interval who had experienced an episode of torsade de pointes. Subsequently, a total of 13 mutation carriers were identified in the family. Carriers (age 48 [26] years; 46% males) underwent clinical evaluation, electrocardiography and echocardiography. The mean (standard deviation) QTc in carriers was 493 (42) ms (3 [23%] showed normal QTc); 6 (46%) had symptoms (4, syncope; 1, sudden death; 1, aborted sudden death [proband]). While under treatment with beta-blockers, 11 of 12 carriers (92%) remained asymptomatic at 5 years of follow-up (1 patient required left cardiac sympathectomy). The QTc shortening with beta-blockers was 50 (37) ms. There was 1 sudden death in a patient who refused treatment. Family study is essential in the interpretation of a genetic testing result. This article describes the heterogeneous and variable phenotype of a large family with the KCNH2-H562R mutation and highlights the role of genetic study for the appropriate identification of at-risk individuals who would benefit from treatment. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

In-Hospital Haloperidol Use and Perioperative Changes in QTc-Duration.

PubMed

Blom, M T; Jansen, S; de Jonghe, A; van Munster, B C; de Boer, A; de Rooij, S E; Tan, H L; van der Velde, N

2015-05-01

Haloperidol may prolong ECG QTc-duration but is often prescribed perioperatively to hip-fracture patients. We aimed to determine (1) how QTc-duration changes perioperatively, (2) whether low-dose haloperidol-use influences these changes, and (3) which clinical variables are associated with potentially dangerous perioperative QTc-prolongation (PD-QTc; increase >50 ms or to >500 ms). Prospective cohort study. Tertiary university teaching-hospital. Patients enrolled in a randomized controlled clinical trial of melatonin versus placebo on occurrence of delirium in hip-fracture patients. Data from ECGs made before and after hip surgery (1-3 days and/or 4-6 days post-surgery) were analyzed. QTc-duration was measured by hand, blinded for haloperidol and pre/post-surgery status. Clinical variables were measured at baseline. Mixed model analysis was used to estimate changes in QTc-duration. Risk-factors for PD-QTc were estimated by logistic regression analysis. We included 89 patients (mean age 84 years, 24% male); 39 were treated with haloperidol. Patients with normal pre-surgery QTc-duration (male ≤430 ms, female ≤450 ms) had a significant increase (mean 12 ms, SD 28) in QTc-duration. A significant decrease (mean 19 ms, SD 34) occurred in patients with prolonged pre-surgery QTc-duration (male >450ms, female >470 ms). Haloperidol-use did not influence the perioperative course of the QTc-interval (p=0.351). PD-QTc (n=8) was not associated with any of the measured risk-factors. QTc-duration changed differentially, increasing in patients with normal, but decreasing in patients with abnormal baseline QTc-duration. PD-QTc was not associated with haloperidol-use or other risk-factors. Low-dose oral haloperidol did not affect perioperative QTc-interval.

Acute coronary syndrome-like presentation with prolonged QT interval: an unusual case of pheochromocytoma.

PubMed

Ozyuncu, Nil; Akturk, Sevinc; Tan Kurklu, Turkan Seda; Erol, Cetin

2016-09-26

Pheochromocytoma is a rare adrenal gland tumour, usually alerting the physician by causing hypertensive tachycardic attacks. Patients with pheochromocytoma can rarely present with clinical signs similar to acute coronary syndrome. QT interval prolongation and ST segment changes due to pheochromocytoma have also been reported in the literature in a few case reports. We report a patient who had been admitted to the emergency department with chest pain, ischaemic ECG changes and marked QT prolongation. Despite a normal coronary angiogram, we observed that the QT interval and ST segment morphologies had changed during the hospitalisation period. Adrenal adenoma was diagnosed incidentally on abdominal CT scan, and the final diagnosis was pheochromocytoma. The tumour was successfully excised and the patient is now symptom free. When there is lack of a typical clinical picture, the diagnosis of pheochromocytoma might be challenging. It is also very crucial, since misdiagnosis can be life-threatening. 2016 BMJ Publishing Group Ltd.

Effects of energy drink consumption on corrected QT interval and heart rate variability in young obese Saudi male university students.

PubMed

Alsunni, Ahmed; Majeed, Farrukh; Yar, Talay; AlRahim, Ahmed; Alhawaj, Ali Fouad; Alzaki, Muneer

2015-01-01

Consumption of energy drinks has adverse effects on the heart that might be potentiated in obese individuals. Since the incidence of obesity and use of energy drinks is high among Saudi youth, we used non-invasive tests to study hemodynamic changes produced by altered autonomic cardiac activ.ity following consumption of energy drinks in obese male students. This cross-sectional study was carried out at Department of Physiology, College of Medicine, University of Dammam, Saudi Arabia, over a one-year period from December 2013 to December 2014. In Saudi male university students we measured continuous ECG recordings and a one-minute deep breathing maneuver to measure the expiratory-to-inspiratory ratio, the mean heart rate range (MHRR), the mean percentage variability. (M%VHR) and the corrected QT interval (QTc) at 0, 30 and 60 minutes after consumption of energy drink. We enrolled 31 students (18 overweight/obese and 13 normal weights. QTc was significantly in.creased at 60 min as compared with the resting state in overweight/obese subjects (P=.006). Heart rate variability was significantly less in obese as compared with normal weight subjects at 60 minutes as indicated by E:I ratio, (P=.037), MHRR (P=.012), M%VHR (P=.040) after energy drink consumption. Significant increases in diastolic (P=.020) and mean arterial blood pressure (P=.024) were observed at 30 minutes in the obese group. Hemodynamic changes after intake of energy drinks in obese subjects indicate that obesity and energy drinks could synergistically induce harmful effects. This finding warrants efforts to caution the obese on intake of energy drinks and timely intervention to motivate changes in lifestyle.

Gene-environment interaction between SCN5A-1103Y and hypokalemia influences QT interval prolongation in African Americans: the Jackson Heart Study.

PubMed

Akylbekova, Ermeg L; Payne, John P; Newton-Cheh, Christopher; May, Warren L; Fox, Ervin R; Wilson, James G; Sarpong, Daniel F; Taylor, Herman A; Maher, Joseph F

2014-01-01

African-American ancestry, hypokalemia, and QT interval prolongation on the electrocardiogram are all risk factors for sudden cardiac death (SCD), but their interactions remain to be characterized. SCN5A-1103Y is a common missense variant, of African ancestry, of the cardiac sodium channel gene. SCN5A-1103Y is known to interact with QT-prolonging factors to promote ventricular arrhythmias in persons at high risk for SCD, but its clinical impact in the general African-American population has not been established. We genotyped SCN5A-S1103Y in 4,476 participants of the Jackson Heart Study, a population-based cohort of African Americans. We investigated the effect of SCN5A-1103Y, including interaction with hypokalemia, on QT interval prolongation, a widely-used indicator of prolonged myocardial repolarization and predisposition to SCD. We then evaluated the two sub-components of the QT interval: QRS duration and JT interval. The carrier frequency for SCN5A-1103Y was 15.4%. SCN5A-1103Y was associated with QT interval prolongation (2.7 milliseconds; P < .001) and potentiated the effect of hypokalemia on QT interval prolongation (14.6 milliseconds; P = .02). SCN5A-1103Y had opposing effects on the two sub-components of the QT interval, with shortening of QRS duration (-1.5 milliseconds; P = .001) and prolongation of the JT interval (3.4 milliseconds; P < .001). Hypokalemia was associated with diuretic use (78%; P < .001). SCN5A-1103Y potentiates the effect of hypokalemia on prolonging myocardial repolarization in the general African-American population. These findings have clinical implications for modification of QT prolonging factors, such as hypokalemia, in the 15% of African Americans who are carriers of SCN5A-1103Y. © 2014.

Assessment of the QT interval in the electroencephalography (EEG) of children with syncope, epilepsy, and attention-deficit hyperactivity disorder (ADHD).

PubMed

Jha, Om P; Khurana, Divya S; Carvalho, Karen S; Melvin, Joseph J; Legido, Agustin; O'Riordan, Anna C; Valencia, Ignacio

2010-03-01

The interpretation of QT interval is often neglected during electroencephalography (EEG) reading. We compared the incidence of prolonged QT interval, as seen in the electrocardiography (ECG) recording lead of the EEG, in children presenting with seizure, syncope, or attention-deficit hyperactivity disorder (ADHD). Abnormal QT was defined as >460 ms. The incidence of prolonged QT in the seizure, syncope, and ADHD groups was 1/50 (2%), 7/50 (14%), and 2/50 (4%), respectively (P = .036, chi-square). The mean +/- SD of QT were 405 +/- 34, 424 +/- 39, and 414 +/- 36, respectively (P = .035, analysis of variance [ANOVA], syncope group, compared with seizure group). The incidence of prolonged QT as measured in the EEG was unexpectedly high in children presenting with seizure, syncope, or ADHD. These data support the concept that QT evaluation should be emphasized during routine EEG reading, as it may aid in identifying cases of undiagnosed cardiac conduction abnormalities. Prospective studies comparing EEG-ECG tracings with 12-lead ECG are warranted.

Effect of Left Cardiac Sympathetic Denervation on the Electromechanical Window in Patients with either Type 1 or Type 2 Long QT Syndrome: A Pilot Study.

PubMed

Schneider, Andrew E; Bos, J Martijn; Ackerman, Michael J

2016-09-01

Left cardiac sympathetic denervation (LCSD) exerts significant antifibrillatory effects in patients with long QT syndrome (LQTS). Recently, electromechanical window (EMW) has emerged as a novel torsadogenic marker in LQTS, superior to QT interval (QTc) in distinguishing symptomatic from asymptomatic patients. To explore the hypothesis that LCSD improves EMW most favorably in patients with LQT1. From September 2006 to July 2015, 44 LQT1 and 25 LQT2 patients underwent LCSD. Subset analysis was performed on the six LQT1 and seven LQT2 patients who had echocardiograms both pre-LCSD and ≥3 months post-LCSD. EMW is defined as the time difference (ms) between aortic valve closure and the end of the QT interval, measured from an ECG on the concurrent echocardiogram. Compared to published normal EMW values of 22 ± 19 ms, pre-LCSD EMW mean values were -78 ± 36 ms in LQT1 and -71 ± 35 ms in LQT2 (P < .001). Following LCSD, there was a 57 ± 35 ms decrease in QTc in LQT1 (P = .16) and 23 ± 21 ms decrease in QTc in LQT2 (P = .3). Overall, there was a 35 ± 57 ms mean improvement in EMW post-LCSD (P = .04). Five of the 6 (83%) LQT1 subjects had a favorable EMW change post-LCSD (mean improvement 56 ± 25 ms, P = .04). Five of the 7 (71%) LQT2 subjects had a favorable EMW change post-LCSD (mean improvement 18 ± 19 ms, P = .2). The precise mechanism of the LCSD therapeutic effect in LQTS patients is not fully understood. This pilot study raises the possibility that LCSD's antitorsadogenic effect in patients with LQT1 could be conferred in part by restoration of electromechanical order, evidenced by normalization of the EMW. © 2016 Wiley Periodicals, Inc.

A case report of QT prolongation with glycopyrronium bromide in a patient with chronic tamoxifen use.

PubMed

Chiu, Michael H; Al-Majed, Nawaf S; Stubbins, Ryan; Pollmann, Dylan; Sandhu, Roopinder K

2016-06-14

Glycopyrronium bromide has recently been approved as a once daily maintenance inhalation therapy for moderate to severe chronic obstructive pulmonary disease (COPD). Efficacy and safety trial data have found rare cases of significant QT prolongation. To our knowledge, we describe the first case report of QT prolongation >600 ms with initiation of glycopyrronium bromide in a real world setting. A 78-year-old female with moderate COPD recently started on glycopyrronium bromide, presented to Emergency Department (ED) with syncope. Her past medical history was significant for a left total mastectomy and she had been on Tamoxifen for 9 months. One day prior to her presentation, she had visited a naturopathic clinic for a vitamin infusion resulting in emesis. The following day she continued to feel dizzy and had a witnessed syncopal episode without any reported cardiac or neurological symptoms preceding the event or after regaining consciousness. In the emergency department, she reported dizziness and was found to be hypotensive. Her symptoms completely resolved with intravenous fluids. Lab work was normal however her electrocardiogram (ECG) demonstrated a QTc interval of 603 and 631 ms (Friderica and Bazett's respectively) with a normal QT interval on her baseline ECG prior to initiating Tamoxifen. She was admitted to the Cardiology service for further work-up of QT prolongation. Her syncope was felt to be due to orthostatic hypotension and the QT prolongation secondary to medications, which were both discontinued during her admission. After 2 days, her QT interval normalized consistent with the half-life of Glycopyrronium bromide (13-57 h) compared to Tamoxifen (8-14 days). Glycopyrronium bromide is guideline recommended as first line therapy for prevention of exacerbation in moderate to severe COPD however safety data had been limited to select populations. This case report highlights the need for future studies to identify high-risk populations at potential

Population Genetic-Based Pharmacokinetic Modeling of Methadone and its Relationship with the QTc Interval in Opioid-Dependent Patients.

PubMed

Csajka, Chantal; Crettol, Séverine; Guidi, Monia; Eap, Chin B

2016-12-01

Methadone is a μ-opioid agonist widely used for the treatment of pain, and for detoxification or maintenance treatment in opioid addiction. It has been shown to exhibit large pharmacokinetic variability and concentration-QTc relationships. In this study we investigated the relative influence of genetic polymorphism and other variables on the dose concentration-QTc relationship. A population model for methadone enantiomers in 251 opioid-dependent patients was developed using non-linear mixed effect modeling (NONMEM ® ). Various models were tested to characterize the pharmacokinetics of (R)- and (S)-methadone and the pharmacokinetic-pharmacodynamic relationship, while including demographics, physiological conditions, co-medications, and genetic variants as covariates. Model-based simulations were performed to assess the relative increase in QTc with dose upon stratification according to genetic polymorphisms involved in methadone disposition. A two-compartment model with first-order absorption and lag time provided the best model fit for (R)- and (S)-methadone pharmacokinetics. (S)-methadone clearance was influenced by cytochrome P450 (CYP) 2B6 activity, ABCB1 3435C>T, and α-1 acid glycoprotein level, while (R)-methadone clearance was influenced by CYP2B6 activity, POR*28, and CYP3A4*22. A linear model described the methadone concentration-QTc relationship, with a mean QTc increase of 9.9 ms and 19.2 ms per 1000 ng/ml of (R)- and (S)-methadone, respectively. Simulations with different methadone doses up to 240 mg/day showed that <8 % of patients presented with a QTc interval above 450 ms; however, this might reach 12 to 18 % for (R)- and (S)-methadone, respectively, in patients with a genetic status associated with a decreased methadone elimination at doses exceeding 240 mg/day. Risk factor assessment, electrocardiogram monitoring, and therapeutic drug monitoring are beneficial to optimize treatment in methadone patients, especially for those who have low

Aldosterone-to-Renin Ratio Is Associated With Reduced 24-Hour Heart Rate Variability and QTc Prolongation in Hypertensive Patients

PubMed Central

Grübler, Martin R.; Kienreich, Katharina; Gaksch, Martin; Verheyen, Nicolas; Hartaigh, Bríain Ó.; Fahrleitner-Pammer, Astrid; März, Winfried; Schmid, Johannes; Oberreither, Eva-Maria; Wetzel, Julia; Catena, Cristiana; Sechi, Leonardo A.; Pieske, Burkert; Tomaschitz, Andreas; Pilz, Stefan

2016-01-01

Abstract Aldosterone is considered to exert direct effects on the myocardium and the sympathetic nervous system. Both QT time and heart rate (HR) variability (HRV) are considered to be markers of arrhythmic risk and autonomous dysregulation. In this study, we investigated the associations between aldosterone, QT time, and HRV in patients with arterial hypertension. We recruited 477 hypertensive patients (age: 60.2 ± 10.2 years; 52.3% females) with a mean systolic/diastolic 24-hour ambulatory blood pressure monitoring (ABPM) value of 128 ± 12.8/77.1 ± 9.2 mmHg and with a median of 2 (IQR: 1–3) antihypertensive agents. Patients were recruited from the outpatient clinic at the Department of Internal Medicine of the Medical University of Graz, Austria. Blood samples, 24-hour HRV derived from 24-hour blood pressure monitoring (ABPM) and ECG's were obtained. Plasma aldosterone and plasma renin concentrations were measured by means of a radioimmunoassay. Twenty-four-hour urine specimens were collected in parallel with ABPM. Mean QTc was 423.3 ± 42.0 milliseconds for males and 434.7 ± 38.3 milliseconds for females. Mean 24H-HR and 24H-HRV was 71.9 ± 9.8 and 10.0 ± 3.6 bpm, respectively. In linear regression analyses adjusted for age, sex, body mass index, ABPM, and current medication, aldosterone to active renin ratio (AARR) was significantly associated with the QTc interval, a marker for cardiac repolarization abnormalities (mean = 426 ± 42.4 milliseconds; β-coefficient = 0.121; P = 0.03) as well as with the 24-hour heart rate variability a surrogate for autonomic dysfunction (median = 9.67 [IQR = 7.38–12.22 bpm]; β-coefficient = −0.133; P = 0.01). In hypertensive patients, AARR is significantly related to QTc prolongation as well as HRV. Further studies investigating the effects of mineralocorticoid receptor blocker and aldosterone synthase inhibitors on QTc and HRV are warranted

Cardiac conductive disturbance in patients with polycystic ovary syndrome.

PubMed

Huang, Jen-Hung; Tsai, Jen-Chen; Hsu, Ming-I; Chen, Yi-Jen

2010-12-01

Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality of reproductive-aged women and increases the risk of cardiovascular disease. However, the effects of PCOS on electrocardiograms (ECGs) are not fully elucidated. The aim of this study was to evaluate the characteristics of ECGs in patients with PCOS. This study included 24 patients with PCOS and 12 patients without PCOS. The heart rate, PR interval, QRS duration, Sokolow-Lyon voltage (SV1 + RV5/6), Cornell voltage (RaVL + SV3), QT interval and QTc interval were measured in 12-lead ECGs. The QRS duration was wider in patients with PCOS than those without PCOS (91 ± 8 vs. 81 ± 10 ms, p < 0.05). The heart rate, PR interval, Sokolow-Lyon voltage, product of the QRS duration times Cornell voltage combination, QT interval, QTc interval, QT dispersion and QTc dispersion were similar between the two groups. PCOS is associated with a widening QRS duration, which may contribute to its increased cardiovascular risks.

Presence or Absence of QTc Prolongation in Buprenorphine-Naloxone Among Youth With Opioid Dependence.

PubMed

Poole, Sabrina A; Pecoraro, Anna; Subramaniam, Geetha; Woody, George; Vetter, Victoria L

2016-01-01

The aim of the study was to evaluate buprenorphine-naloxone effects on the QTc in youth with opioid dependence. Buprenorphine is a partial agonist that is an effective treatment for opioid dependence. Compared with methadone, it has a lower risk of QTc prolongation in adults, but is less studied in the youth. It may also reduce the risk of torsades de pointes (TdP)--an uncommon variant of polymorphic ventricular tachycardia--that can result in syncope, ventricular fibrillation, and sudden death. Secondary analysis of the electrocardiogram data from 95 individuals who participated in a multisite trial for youth with opioid dependence. The participants were randomized to a 2-week (DETOX) or a 12-week course of buprenorphine-naloxone (BUP). At baseline, 12-lead electrocardiograms were done at weeks 4 and 12, and QTc intervals were hand-measured and calculated using Bazett formula. Increases above 60 milliseconds were considered clinically significant, and readings above 450 milliseconds (in men) and 470 milliseconds (in women) indicated a prolonged QTc. Mean QTc intervals were higher for BUP than for DETOX participants at baseline, week 4, and week 12 (P = 0.045), and women had longer mean QTc intervals than men (P < 0.0005). Variations in the QTc intervals were observed in some; however, none were above 500 milliseconds--the level at which risk for TdP becomes more significant. In this randomized trial, the mean QTc at baseline, before randomization, was higher in BUP than in DETOX patients. Minimal changes in the QTc were seen at 4 and 12 weeks in a few patients in both groups. There was no evidence that buprenorphine-naloxone alone increased the QTc to a level that increased the risk for TdP.

Timothy syndrome-like condition with syndactyly but without prolongation of the QT interval.

PubMed

Kosaki, Rika; Ono, Hiroshi; Terashima, Hiroshi; Kosaki, Kenjiro

2018-05-07

Timothy syndrome is characterized by a unique combination of a prolongation of the corrected QT interval of the electrocardiogram and bilateral cutaneous syndactyly of the fingers and the toes and is caused by heterozygous mutations in CACNA1C, a gene encoding a calcium channel. After the discovery of the CACNA1C gene as the causative gene for Timothy syndrome, patients with CACNA1C mutations with QT prolongation but without syndactyly were described. Here, we report a 5-year-old female patient with cutaneous syndactyly, developmental delay, and pulmonary hypertension. Exome analysis showed a previously undescribed de novo heterozygous mutation in the CACNA1C gene, p.Arg1024Gly. To our knowledge, this patient is the first to exhibit syndactyly and to carry a CACNA1C mutation but to not have QT prolongation, which has long been considered an obligatory feature of Timothy syndrome. © 2018 Wiley Periodicals, Inc.

The Presence or Absence of QTc Prolongation in Buprenorphine-Naloxone Among Youth with Opioid Dependence

PubMed Central

Poole, Sabrina A.; Pecoraro, Anna; Subramaniam, Geetha; Woody, George; Vetter, Victoria L

2015-01-01

Objective To evaluate buprenorphine-naloxone effects on the QTc in youth with opioid dependence. Buprenorphine is a partial agonist that is an effective treatment for opioid dependence. Compared to methadone it has a lower risk of QTc prolongation in adults but is less well studied in youth. It may also reduce the risk for torsades de pointes (TdP) an uncommon variant of polymorphic ventricular tachycardia, that can result in syncope, ventricular fibrillation, and sudden death. Methods Secondary analysis of ECG data from 95 subjects who participated in a multi-site trial for youth with opioid dependence. Subjects were randomized to a 2-week (DETOX), or a 12-week course of buprenorphine-naloxone (BUP). 12-lead ECGs were done at baseline, weeks 4 and 12, and QTc intervals were hand measured and calculated using Bazett's formula. Increases > 60 milliseconds (ms) were considered clinically significant, and readings > 450 ms (males) and 470 ms (females) indicated a prolonged QTc. Results Mean QTc intervals were higher for BUP than DETOX participants at baseline, week 4, and week 12 (p = 0.045), and females had longer mean QTc intervals than males (p < 0.0005). Variations in QTc intervals were observed in some, however none were above 500 ms, the level at which risk for TdP becomes more significant. Conclusion In this randomized trial, the mean QTc at baseline, before randomization, was higher in BUP than DETOX patients. Minimal changes in the QTc were seen at 4 and 12-weeks in a few patients in both groups. There was no evidence that buprenorphine-naloxone alone increased the QTc to a level that increased the risk for TdP. PMID:26690291

Characterization of Myocardial Repolarization Reserve in Adolescent Females With Anorexia Nervosa.

PubMed

Padfield, Gareth J; Escudero, Carolina A; DeSouza, Astrid M; Steinberg, Christian; Gibbs, Karen; Puyat, Joseph H; Lam, Pei Yoong; Sanatani, Shubhayan; Sherwin, Elizabeth; Potts, James E; Sandor, George; Krahn, Andrew D

2016-02-09

Patients with anorexia nervosa exhibit abnormal myocardial repolarization and are susceptible to sudden cardiac death. Exercise testing is useful in unmasking QT prolongation in disorders associated with abnormal repolarization. We characterized QT adaptation during exercise in anorexia. Sixty-one adolescent female patients with anorexia nervosa and 45 age- and sex-matched healthy volunteers performed symptom-limited cycle ergometry during 12-lead ECG monitoring. Changes in the QT interval during exercise were measured, and QT/RR-interval slopes were determined by using mixed-effects regression modeling. Patients had significantly lower body mass index than controls; however, resting heart rates and QT/QTc intervals were similar at baseline. Patients had shorter exercise times (13.7±4.5 versus 20.6±4.5 minutes; P<0.001) and lower peak heart rates (159±20 versus 184±9 beats/min; P<0.001). The mean QTc intervals were longer at peak exercise in patients (442±29 versus 422±19 ms; P<0.001). During submaximal exertion at comparable heart rates (114±6 versus 115±11 beats/min; P=0.54), the QTc interval had prolonged significantly more in patients than controls (37±28 versus 24±25 ms; P<0.016). The RR/QT slope, best described by a curvilinear relationship, was more gradual in patients than in controls (13.4; 95% confidence interval, 12.8-13.9 versus 15.8; 95% confidence interval, 15.3-16.4 ms QT change per 10% change in RR interval; P<0.001) and steepest in patients within the highest body mass index tertile versus the lowest (13.9; 95% confidence interval, 12.9-14.9 versus 12.3; 95% confidence interval, 11.3-13.3; P=0.026). Despite the absence of manifest QT prolongation, adolescent anorexic females have impaired repolarization reserve in comparison with healthy controls. Further study may identify impaired QT dynamics as a risk factor for arrhythmias in anorexia nervosa. © 2016 American Heart Association, Inc.

CYP2C19 variation, not citalopram dose nor serum level, is associated with QTc prolongation.

PubMed

Kumar, Yingying; Kung, Simon; Shinozaki, Gen

2014-12-01

Recently, a FDA Safety Communication warned of a dose-dependent risk for QTc prolongation with citalopram, which is metabolized by CYP2C19 of the cytochrome P450 system. We investigate associations between citalopram and escitalopram dose, serum concentration, CYP2C19 phenotype, and QTc. We undertook a retrospective chart review of citalopram or escitalopram patients with the inclusion criteria of consistent medication dose, CYP2C19 phenotype (extensive metabolizers [EM], intermediate metabolizers [IM], poor metabolizers [PM]), and QTc interval on ECG. We further identified 42 citalopram users with citalopram serum concentration measurements and ECG. Regression and one-way ANOVA were used to examine the relationship between citalopram dose, citalopram serum concentration, CYP2C19 phenotype, and QTc interval. Of 75 citalopram patients, the EM group had significantly shorter QTc intervals than a combined IM+PM group (427.1±23.6 ms vs. 440.1±26.6 ms, one-tailed t-test, p=0.029). In the 80 escitalopram cohort, there was no significant difference in QTc between phenotype groups. There was no statistical correlation between citalopram (p=0.62) or escitalopram (p=0.30) dose and QTc. QTc was not associated with citalopram serum level (p=0.45). In contrast to the FDA warning, this study found no association between citalopram/escitalopram dose and QTc. However, PM of the drug tended to have longer QTc intervals. Our findings suggest cytochrome P450 genotyping in select patients may be helpful to guide medication optimization while limiting harmful effects. © The Author(s) 2014.

Abnormal myocardial repolarisation in response to hypoxaemia and fenoterol.

PubMed Central

Kiely, D. G.; Cargill, R. I.; Grove, A.; Struthers, A. D.; Lipworth, B. J.

1995-01-01

BACKGROUND--Prolongation of the QTc interval has been associated with cardiac dysrhythmias and sudden death. QTc dispersion (interlead variability in QTc interval) has recently been proposed as being a more sensitive marker of repolarisation abnormalities and shown to be a more specific index of arrhythmia risk. Although hypoxaemia and fenoterol have previously been shown to prolong the QTc interval, this does not reflect regional myocardial repolarisation abnormalities. METHODS--Electrophysiological effects were measured at baseline and after 30 minutes steady state hypoxaemia at an arterial oxygen saturation (SaO2) of 75-80% (study 1) and at baseline then 30 minutes after inhaled fenoterol 2.4 mg (study 2). From the ECG, lead II corrected QT interval (QTc) and overall corrected QT dispersion were measured using a computer linked digitising tablet according to standard criteria. RESULTS--QTc dispersion was increased during hypoxia compared with baseline values (mean (SE) 69 (6) ms v 50 (5) ms) and after fenoterol compared with baseline (79 (13) v 46 (4) ms), respectively. There was also an increase in QTc interval and heart rate after fenoterol (493 (23) v 420 (6) ms and 98 (3) v 71 (6) bpm, respectively). The heart rate was increased during hypoxaemia compared with baseline (78 (3) v 64 (2) bpm), but no change occurred in the QTc interval. CONCLUSIONS--Both hypoxaemia and fenoterol cause myocardial repolarisation abnormalities in man in terms of increased QTc dispersion, but only fenoterol increased the QTc interval. This may be relevant in the aetiology of arrhythmias in patients with acute severe asthma where beta agonist therapy and hypoxaemia coexist. PMID:7491554

A new approach to correct the QT interval for changes in heart rate using a nonparametric regression model in beagle dogs.

PubMed

Watanabe, Hiroyuki; Miyazaki, Hiroyasu

2006-01-01

Over- and/or under-correction of QT intervals for changes in heart rate may lead to misleading conclusions and/or masking the potential of a drug to prolong the QT interval. This study examines a nonparametric regression model (Loess Smoother) to adjust the QT interval for differences in heart rate, with an improved fitness over a wide range of heart rates. 240 sets of (QT, RR) observations collected from each of 8 conscious and non-treated beagle dogs were used as the materials for investigation. The fitness of the nonparametric regression model to the QT-RR relationship was compared with four models (individual linear regression, common linear regression, and Bazett's and Fridericia's correlation models) with reference to Akaike's Information Criterion (AIC). Residuals were visually assessed. The bias-corrected AIC of the nonparametric regression model was the best of the models examined in this study. Although the parametric models did not fit, the nonparametric regression model improved the fitting at both fast and slow heart rates. The nonparametric regression model is the more flexible method compared with the parametric method. The mathematical fit for linear regression models was unsatisfactory at both fast and slow heart rates, while the nonparametric regression model showed significant improvement at all heart rates in beagle dogs.

Effects of anti-malarial drugs on the electrocardiographic QT interval modelled in the isolated perfused guinea pig heart system

PubMed Central

2010-01-01

Background Concern over the potential cardiotoxicity of anti-malarial drugs inducing a prolonged electrocardiographic QT interval has resulted in the almost complete withdrawal from the market of one anti-malarial drug - halofantrine. The effects on the QT interval of four anti-malarial drugs were examined, using the guinea pig heart. Methods The guinea pig heart was isolated, mounted on a Langendorff apparatus, and was then perfused with pyruvate-added Klebs-Henseleit solutions containing graded concentrations of the four agents such as quinidine (0.15 - 1.2 μM), quinine (0.3 - 2.4 μM), halofantrine (0.1 - 2.0 μM) and mefloquine (0.1 - 2.0 μM). The heart rate-corrected QaTc intervals were measured to evaluate drug-induced QT prolongation effects. Results Quinidine, quinine, and halofantrine prolonged the QaTc interval in a dose-dependent manner, whereas no such effect was found with mefloquine. The EC50 values for the QaTc prolongation effects, the concentration that gives a half-maximum effect, were quinidine < quinine ≈ halofantrine. Conclusions In this study, an isolated, perfused guinea pig heart system was constructed to assess the cardiotoxic potential of anti-malarial drugs. This isolated perfused guinea pig heart system could be used to test newly developed anti-malarial drugs for their inherent QT lengthening potential. More information is required on the potential variation in unbound drug concentrations in humans, and their role in cardiotoxicity. PMID:21067575

A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation.

PubMed

Bartos, Daniel C; Giudicessi, John R; Tester, David J; Ackerman, Michael J; Ohno, Seiko; Horie, Minoru; Gollob, Michael H; Burgess, Don E; Delisle, Brian P

2014-03-01

Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1-encoded Kv7.1 channel that conducts the slowly activating component of the delayed rectifier K(+) current (IKs). Clinically, the diagnosis of LQT1 is complicated by variable phenotypic expressivity, whereby approximately 25% of genotype-positive individuals present with concealed LQT1 (resting corrected QT [QTc] interval ≤460 ms). To determine whether a specific molecular mechanism contributes to concealed LQT1. We identified a multigenerational LQT1 family whereby 79% of the patients genotype-positive for p.Ile235Asn-KCNQ1 (I235N-Kv7.1) have concealed LQT1. We assessed the effect I235N-Kv7.1 has on IKs and the ventricular action potential (AP) by using in vitro analysis and computational simulations. Clinical data showed that all 10 patients with I235N-Kv7.1 have normal resting QTc intervals but abnormal QTc interval prolongation during the recovery phase of an electrocardiographic treadmill stress test. Voltage-clamping HEK293 cells coexpressing wild-type Kv7.1 and I235N-Kv7.1 (to mimic the patients' genotypes) showed that I235N-Kv7.1 generated relatively normal functioning Kv7.1 channels but were insensitive to protein kinase A (PKA) activation. Phosphomimetic and quinidine sensitivity studies suggest that I235N-Kv7.1 limits the conformational changes in Kv7.1 channels, which are necessary to upregulate IKs after PKA phosphorylation. Computational ventricular AP simulations predicted that the PKA insensitivity of I235N-Kv7.1 is primarily responsible for prolonging the AP with β-adrenergic stimulation, especially at slower cycle lengths. KCNQ1 mutations that generate relatively normal Kv7.1 channels, but limit the upregulation of IKs by PKA activation, likely contribute to concealed LQT1. Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Long QT syndrome in African-Americans.

PubMed

Fugate, Thomas; Moss, Arthur J; Jons, Christian; McNitt, Scott; Mullally, Jamie; Ouellet, Gregory; Goldenberg, Ilan; Zareba, Wojciech; Robinson, Jennifer L

2010-01-01

We evaluated the risk factors and clinical course of Long QT syndrome (LQTS) in African-American patients. The study involved 41 African-Americans and 3456 Caucasians with a QTc > or = 450 ms from the U.S. portion of the International LQTS Registry. Data included information about the medical history and clinical course of the LQTS patients with end points relating to the occurrence of syncope, aborted cardiac arrest, or LQTS-related sudden cardiac death from birth through age 40 years. The statistical analyses involved Kaplan-Meier time to event graphs and Cox regression models for multivariable risk factor evaluation. The QTc was 29 ms longer in African-Americans than Caucasians. Multivarite Cox analyses with adjustment for decade of birth revealed that the cardiac event rate was similar in African-Americans and Caucasians with LQTS and that beta-blockers were equally effective in reducing cardiac events in the two racial groups. The clinical course of LQTS in African-Americans is similar to that of Caucasians with comparable risk factors and benefit from beta-blocker therapy in the two racial groups.

Stability of the Effect of a Standardized Meal on QTc.

PubMed

Täubel, Jörg; Fernandes, Sara; Ferber, Georg

2017-01-01

The assessment of QTc changes after the intake of a standardized meal has been proposed as an alternative approach to prove assay sensitivity when the proarrhythimic potential of a drug is to be excluded in either TQT or intensive Phase I QT studies. In this article, an analysis of the food effect at baseline across periods in two different studies is presented to support the robustness of the method. The results show that the time-effect attributed to food is stable over different study periods demonstrating consistency of the physiological response triggered by food. Stability and reproducibility of the effect is comparable with moxifloxacin. © 2016 Wiley Periodicals, Inc.

Pharmacokinetics and effect on the corrected QT interval of single-dose escitalopram in healthy elderly compared with younger adults.

PubMed

Chung, Hyewon; Kim, Anhye; Lim, Kyoung Soo; Park, Sang-In; Yu, Kyung-Sang; Yoon, Seo Hyun; Cho, Joo-Youn; Chung, Jae-Yong

2017-01-01

Escitalopram is the (S)-enantiomer of citalopram that has a potential QT prolonging effect. In this study, 12 healthy elderly individuals received a single oral dose of escitalopram (20 mg), and their pharmacokinetics and QT effect data were compared with data from 33 younger adults obtained in a previous study. Serial blood samples for pharmacokinetic analysis were collected and ECG was performed up to 48 h postdose. The elderly and younger adults showed similar pharmacokinetic profiles. The geometric mean ratios (90% confidence interval) of the elderly compared with the younger adults were 1.02 (0.89-1.17) and 1.01 (0.86-1.17) for the maximum plasma concentration and area under the concentration-time curve, respectively. The mean baseline-adjusted QT (dQT) time profiles were similar and the mean values of maximum dQT were not significantly different between the elderly and the younger adults. The linear mixed-effect model indicated a weak but positive relationship between the escitalopram concentration and dQT, with an estimated coefficient of concentration of 0.43-0.54. In conclusion, the pharmacokinetics and QT effect of a single dose of escitalopram observed in the elderly without comorbidities and younger adults were generally similar.

Pharmacogenomics Study of Thiazide Diuretics and QT Interval in Multi-Ethnic Populations: The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE)

PubMed Central

Seyerle, Amanda A; Sitlani, Colleen M; Noordam, Raymond; Gogarten, Stephanie M; Li, Jin; Li, Xiaohui; Evans, Daniel S; Sun, Fangui; Laaksonen, Maarit A; Isaacs, Aaron; Kristiansson, Kati; Highland, Heather M; Stewart, James D; Harris, Tamara B; Trompet, Stella; Bis, Joshua C; Peloso, Gina M; Brody, Jennifer A; Broer, Linda; Busch, Evan L; Duan, Qing; Stilp, Adrienne M; O’Donnell, Christopher J; Macfarlane, Peter W; Floyd, James S; Kors, Jan A; Lin, Henry J; Li-Gao, Ruifang; Sofer, Tamar; Méndez-Giráldez, Raúl; Cummings, Steven R; Heckbert, Susan R; Hofman, Albert; Ford, Ian; Li, Yun; Launer, Lenore J; Porthan, Kimmo; Newton-Cheh, Christopher; Napier, Melanie D; Kerr, Kathleen F; Reiner, Alexander P; Rice, Kenneth M; Roach, Jeffrey; Buckley, Brendan M; Soliman, Elsayed Z; de Mutsert, Renée; Sotoodehnia, Nona; Uitterlinden, André G; North, Kari E; Lee, Craig R; Gudnason, Vilmundur; Stürmer, Til; Rosendaal, Frits R; Taylor, Kent D; Wiggins, Kerri L; Wilson, James G; Chen, Yii-Der I; Kaplan, Robert C; Wilhelmsen, Kirk; Cupples, L Adrienne; Salomaa, Veikko; van Duijn, Cornelia; Jukema, J Wouter; Liu, Yongmei; Mook-Kanamori, Dennis O; Lange, Leslie A; Vasan, Ramachandran S; Smith, Albert V; Stricker, Bruno H; Laurie, Cathy C; Rotter, Jerome I; Whitsel, Eric A; Psaty, Bruce M; Avery, Christy L

2017-01-01

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common SNPs modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic, and cross-phenotype genome-wide analyses of European (66%), African American (15%), and Hispanic (19%) populations (N=78,199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5×10−8), we found suggestive evidence (P<5×10−6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (e.g. NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions. PMID:28719597

QT prolongation and proarrhythmia by moxifloxacin: concordance of preclinical models in relation to clinical outcome

PubMed Central

Chen, Xian; Cass, Jessica D; Bradley, Jenifer A; Dahm, Corinn M; Sun, Zhuoqian; Kadyszewski, Edmund; Engwall, Michael J; Zhou, Jun

2005-01-01

Moxifloxacin, a fluoroquinolone antibiotic associated with QT prolongation, has been recommended as a positive control by regulatory authorities to evaluate the sensitivity of both clinical and preclinical studies to detect small but significant increases in QT interval measurements. In this study, we investigated effects of moxifloxacin on the hERG current in HEK-293 cells, electrocardiograms in conscious telemetered dogs, and repolarization parameters and arrhythmogenic potentials in the arterially perfused rabbit ventricular wedge model. Moxifloxacin inhibited the hERG current with an IC50 of 35.7 μM. In conscious telemetered dogs, moxifloxacin significantly prolonged QTc at 30 and 90 mg kg−1, with mean serum Cmax of 8.52 and 22.3 μg ml−1, respectively. In the wedge preparation, moxifloxacin produced a concentration-dependent prolongation of the action potential duration, QT interval, and the time between peak and end of the T wave, an indicator for transmural dispersion of repolarization. Phase 2 early after-depolarizations were observed in one of five experiments at 30 μM and five of five experiments at 100 μM. The arrhythmogenic potential was also concentration-dependent, and 100 μM (∼18-fold above the typical unbound Cmax exposure in clinical usage) appeared to have a high risk of inducing torsade de pointes (TdP). Our data indicated a good correlation among the concentration–response relationships in the three preclinical models and with the available clinical data. The lack of TdP report by moxifloxacin in patients without other risk factors might be attributable to its well-behaved pharmacokinetic profile and other dose-limiting effects. PMID:16158069

QT variability strongly predicts sudden cardiac death in asymptomatic subjects with mild or moderate left ventricular systolic dysfunction: a prospective study.

PubMed

Piccirillo, Gianfranco; Magrì, Damiano; Matera, Sabrina; Magnanti, Marzia; Torrini, Alessia; Pasquazzi, Eleonora; Schifano, Erika; Velitti, Stefania; Marigliano, Vincenzo; Quaglione, Raffaele; Barillà, Francesco

2007-06-01

The most widely accepted marker for stratifying the risk of sudden cardiac death (SCD) in post myocardial infarction patients is a depressed left ventricular function. Left ventricular ejection fractions (EF) of 35% or less increase the risk of sudden death but values between 35 and 40% raise concern. The underlying pathophysiological mechanism is sustained ventricular tachycardia or fibrillation, both associated with increased cardiac repolarization variability. We assessed whether the indices of QT variability from a short-term electrocardiographic (ECG) recording predict sudden death. A total of 396 subjects with chronic heart failure (CHF) due to post-ischaemic cardiomyopathy, with an EF between 35 and 40% and in NYHA class I, underwent a 5 min ECG recording to calculate the following variables: QT variance (QT(v)), QT normalized for the square of the mean QT (QTVN), and QT variability index (QTVI). Corrected QT (QT(c)) was calculated from a 12-lead ECG recording. All participants were followed for 5 years. A multivariable survival model indicated that a QTVI greater than or equal to the 80th percentile indicated a high risk of SCD [hazards ratio (HR) 4.6, 95% confidence interval (CI) 1.5-13.4, P = 0.006] and, though to a lesser extent, a high risk of total mortality (HR 2.4, 95% CI 1.2-4.9, P = 0.017). The model including QTVI as a continuous variable confirmed a similar high risk for SCD (HR 2.9, 95% CI 1.3-6.5, P = 0.01) and for total mortality (HR 2.6, 95% CI 1.3-5.2, P = 0.008). Although asymptomatic patients with CHF who have a slightly depressed EF are at low risk of sudden death, the category is extraordinarily numerous. The QTVI could be helpful in stratifying the risk of sudden death in this otherwise undertreated population.

The C-allele of tissue inhibitor of metalloproteinases 2 is associated with increased magnitude of QT dispersion prolongation in elderly Chinese - 4-year follow-up study.

PubMed

Lin, Tsung-Hsien; Chiu, Herng-Chia; Lee, Ya-Ting; Su, Ho-Ming; Juo, Suh-Hang Hank; Voon, Wen-Chol; Lai, Wen-Ter; Sheu, Sheng-Hsiung

2007-01-01

Matrix metalloproteinases (MMP) and tissue inhibitor of metalloproteinases (TIMP) trigger the signal cascade instigating cardiac remodeling and fibrosis, which lead to changes of repolarization variables. We investigate the influence of MMP9-1562 C/T and TIMP2-418 G/C gene polymorphisms on repolarization parameters including QT dispersion (QTd) and the peak and the end of the T wave interval (Tpe) in a prospective cohort. Of 1500 people screened, 106 elderly Chinese without organic heart disease were recruited and received electrocardiography at the baseline, second and 4th year follow-ups. The QTc (corrected QT), QTd, QTc dispersion (QTcd) and Tpe were manually calculated. Age was 72.7+/-4.1 y (range 62-81 y). QTd, QTcd and Tpe were significantly prolonged (all p <0.001 at the 2nd and 4th year). At the 4th year the magnitude of QTd prolongation but not Tpe was significantly higher in subjects carrying the TIMP2 C-allele than non C-allele carriers (p=0.033) as well as QTcd (p=0.010). This association was still significant in multivariate analyses (p=0.012 and p=0.003 for QTd and QTcd, respectively) but not in MMP9 genotype. The elderly Chinese with TIMP2 C-allele have higher magnitude of QTd and QTcd prolongation.

Realtime Multichannel System for Beat to Beat QT Interval Variability

NASA Technical Reports Server (NTRS)

Starc, Vito; Schlegel, Todd T.

2006-01-01

The measurement of beat-to-beat QT interval variability (QTV) shows clinical promise for identifying several types of cardiac pathology. However, until now, there has been no device capable of displaying, in real time on a beattobeat basis, changes in QTV in all 12 conventional leads in a continuously monitored patient. While several software programs have been designed to analyze QTV, heretofore, such programs have all involved only a few channels (at most) and/or have required laborious user interaction or offline calculations and postprocessing, limiting their clinical utility. This paper describes a PC-based ECG software program that in real time, acquires, analyzes and displays QTV and also PQ interval variability (PQV) in each of the eight independent channels that constitute the 12lead conventional ECG. The system also processes certain related signals that are derived from singular value decomposition and that help to reduce the overall effects of noise on the realtime QTV and PQV results.

Ranolazine Shortens Repolarization in Patients with Sustained Inward Sodium Current Due To Type-3 Long QT Syndrome

PubMed Central

Moss, Arthur J.; Zareba, Wojciech; Schwarz, Karl Q.; Rosero, Spencer; McNitt, Scott; Robinson, Jennifer L.

2008-01-01

Introduction One form of the hereditary long QT-syndrome, LQT3-ΔKPQ, is associated with sustained inward sodium current during membrane depolarization. Ranolazine reduces late sodium channel current, and we hypothesized that ranolazine would have beneficial effects on electrical and mechanical cardiac function in LQT3 patients with the SCN5A-ΔKPQ mutation. Methods We assessed the effects of 8-hour intravenous ranolazine infusions (45mg/hr for 3 hours followed by 90mg/hr for 5 hours) on ventricular repolarization and myocardial relaxation in five LQT3 patients with the SCN5A-ΔKPQ mutation. Changes in electrocardiographic QTc parameters from before to during ranolazine infusion were evaluated by time-matched, paired t-test analyses. Cardiac ultrasound recordings were obtained before ranolazine infusion and just before completion of the 8-hour ranolazine infusion. Results Ranolazine shortened QTc by 26±3ms (p<0.0001) in a concentration-dependent manner. At peak ranolazine infusion, there was a significant 13% shortening in left ventricular isovolumic relaxation time, a significant 25% increase in mitral E-wave velocity, and a meaningful 22% decrease in mitral E-wave deceleration time compared to baseline. No adverse effects of ranolazine were observed in the study patients. Conclusion Ranolazine at therapeutic concentrations shortened a prolonged QTc interval and improved diastolic relaxation in patients with the LQT3-ΔKPQ mutation, a genetic disorder that is known to cause an increase of late sodium current. PMID:18662191

Prolonged QT Syndrome and Seizure Secondary to Alkaline Earth Metal Deficiency: A Case Report.

PubMed

McKinney, A; Keegan, B C

2011-01-01

Introduction. Alkaline earth metal deficiency is recognized as a cause of both seizure and long QT syndrome. Their deficiency can have significant repercussions on the function of cells, tissues, and organs of the body. An understanding of the role of electrolytes allows an appreciation of the significance of depleted levels on cell function. Case Report. A 65-year-old lady was admitted with symptoms of chest discomfort, vomiting, increased stoma output, and dizziness. Two days following admission she suffered a tonic-clonic seizure. ECG review demonstrated a prolonged QTc interval, raising the possibility of an underlying Torsades de Pointes as the precipitant. This was attributed to electrolyte disturbance arising as a result of multiple aetiologies. Discussion. This paper highlights the multisystem effects of electrolyte disturbance, with emphasis upon its role in precipitating cardiac arrhythmia and neurological symptoms.

Behavioral Hyperventilation and Central Sleep Apnea in Two Children.

PubMed

Johnston, Thomas P; Tam-Williams, Jade; Schmandt, Margaret; Patel, Anand C; Cleveland, Claudia; Coste, Ferdinand; Kemp, James S

2015-04-01

Behavioral hyperventilation is a rarely recognized cause of central sleep apnea (CSA) among children. We report two pediatric patients who presented with prolonged central sleep apnea secondary to behavioral hyperventilation. One patient also had a prolonged corrected QT (QT(C)) interval resulting from hyperventilation

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval--A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity.

PubMed

Täubel, Jörg; Ferber, Georg; Lorch, Ulrike; Wang, Duolao; Sust, Mariano; Camm, A John

2015-01-01

E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects. Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day). In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis. The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal. EU Clinical Trials Register EudraCT 2010 020343 13.

T-wave morphology can distinguish healthy controls from LQTS patients.

PubMed

Immanuel, S A; Sadrieh, A; Baumert, M; Couderc, J P; Zareba, W; Hill, A P; Vandenberg, J I

2016-09-01

Long QT syndrome (LQTS) is an inherited disorder associated with prolongation of the QT/QTc interval on the surface electrocardiogram (ECG) and a markedly increased risk of sudden cardiac death due to cardiac arrhythmias. Up to 25% of genotype-positive LQTS patients have QT/QTc intervals in the normal range. These patients are, however, still at increased risk of life-threatening events compared to their genotype-negative siblings. Previous studies have shown that analysis of T-wave morphology may enhance discrimination between control and LQTS patients. In this study we tested the hypothesis that automated analysis of T-wave morphology from Holter ECG recordings could distinguish between control and LQTS patients with QTc values in the range 400-450 ms. Holter ECGs were obtained from the Telemetric and Holter ECG Warehouse (THEW) database. Frequency binned averaged ECG waveforms were obtained and extracted T-waves were fitted with a combination of 3 sigmoid functions (upslope, downslope and switch) or two 9th order polynomial functions (upslope and downslope). Neural network classifiers, based on parameters obtained from the sigmoid or polynomial fits to the 1 Hz and 1.3 Hz ECG waveforms, were able to achieve up to 92% discrimination between control and LQTS patients and 88% discrimination between LQTS1 and LQTS2 patients. When we analysed a subgroup of subjects with normal QT intervals (400-450 ms, 67 controls and 61 LQTS), T-wave morphology based parameters enabled 90% discrimination between control and LQTS patients, compared to only 71% when the groups were classified based on QTc alone. In summary, our Holter ECG analysis algorithms demonstrate the feasibility of using automated analysis of T-wave morphology to distinguish LQTS patients, even those with normal QTc, from healthy controls.

Single Doses up to 800 mg of E-52862 Do Not Prolong the QTc Interval – A Retrospective Validation by Pharmacokinetic-Pharmacodynamic Modelling of Electrocardiography Data Utilising the Effects of a Meal on QTc to Demonstrate ECG Assay Sensitivity

PubMed Central

Täubel, Jörg; Ferber, Georg; Lorch, Ulrike; Wang, Duolao; Sust, Mariano; Camm, A. John

2015-01-01

Background E-52862 is a Sigma-1 receptor antagonist (S1RA) currently under investigation as a potential analgesic medicine. We successfully applied a concentration-effect model retrospectively to a four-way crossover Phase I single ascending dose study and utilized the QTc shortening effects of a meal to demonstrate assay sensitivity by establishing the time course effects from baseline in all four periods, independently from any potential drug effects. Methods Thirty two healthy male and female subjects were included in four treatment periods to receive single ascending doses of 500 mg, 600 mg or 800 mg of E-52862 or placebo. PK was linear over the dose range investigated and doses up to 600 mg were well tolerated. The baseline electrocardiography (ECG) measurements on Day-1 were time-matched with ECG and pharmacokinetic (PK) samples on Day 1 (dosing day). Results In this conventional mean change to time-matched placebo analysis, the largest time-matched difference to placebo QTcI was 1.44 ms (90% CI: -4.04, 6.93 ms) for 500 mg; -0.39 ms (90% CI: -3.91, 3.13 ms) for 600 mg and 1.32 ms (90% CI: -1.89, 4.53 ms) for 800 mg of E-52862, thereby showing the absence of any QTc prolonging effect at the doses tested. In addition concentration-effect models, one based on the placebo corrected change from baseline and one for the change of QTcI from average baseline with time as fixed effect were fitted to the data confirming the results of the time course analysis. Conclusion The sensitivity of this study to detect small changes in the QTc interval was confirmed by demonstrating a shortening of QTcF of -8.1 (90% CI: -10.4, -5.9) one hour and -7.2 (90% CI: -9.4, -5.0) three hours after a standardised meal. Trial Registration EU Clinical Trials Register EudraCT 2010 020343 13 PMID:26291080

QTc Prolongation in Veterans With Heroin Dependence on Methadone Maintenance Treatment.

PubMed

Hassamal, Sameer; Fernandez, Antony; Moradi Rekabdarkolaee, Hossein; Pandurangi, Ananda

2015-06-01

QTc prolongation and Torsade de Ppointes have been reported in patients on methadone maintenance. In this study, QTc was compared before and after the veteran (n = 49) was on a stable dosage of methadone for 8.72 ± 4.50 years to treat heroin dependence. Risk factors were correlated with the QTc once the veteran was on a stable dose of methadone. Differences in the clinical risk factors in subgroups of veterans with below and above mean QTc change was compared. ECG data was obtained from a 12-lead electrocardiogram (pre-methadone and on methadone) on 49 veterans. Data and risk factors were retrospectively collected from the medical records. The mean QTc at baseline (pre-methadone) was 426 ± 34 msec and after being on methadone for an average of 8.72 ± 4.50 years was significantly higher at 450 ± 35 msec. No significant relationships were found between QTc prolongation and risk factors except for calcium. The methadone dosage was significantly higher in veterans with a QTc change above the mean change of ≥ 24 msec (88.48 ± 27.20 mg v.s 68.96 ± 19.84 mg). None of the veterans experienced cardiac arrhythmias. The low complexity of medical co-morbidities may explain the lack of a significant correlation between any risk factor with the QTc except calcium and methadone dosage. The absence of TdP may be explained by the low prevalence of QTc values > 500 msec as well as the retrospective design of the study. During long-term methadone treatment, there was a slight increase in the QTc interval but we did not find evidence of increased cardiac toxicity as a reason for treatment termination.

Long-term high-intensity interval training associated with lifestyle modifications improves QT dispersion parameters in metabolic syndrome patients.

PubMed

Drigny, J; Gremeaux, V; Guiraud, T; Gayda, M; Juneau, M; Nigam, A

2013-07-01

QT dispersion (QTd) is a marker of myocardial electrical instability, and is increased in metabolic syndrome (MetS). Moderate intensity continuous exercise (MICE) training was shown to improve QTd in MetS patients. To describe long-term effects of MICE and high-intensity interval exercise training (HIIT) on QTd parameters in MetS. Sixty-five MetS patients (53 ± 9 years) were assigned to either a MICE (60% of peak power output [PPO]), or a HIIT program (alternating phases of 15-30 s at 80% of PPO interspersed by passive recovery phases of equal duration), twice weekly during 9 months. Ventricular repolarization indices (QT dispersion=QTd, standard deviation of QT = sdQT, relative dispersion of QT = rdQT, QT corrected dispersion = QTcd), metabolic, anthropometric and exercise parameters were measured before and after the intervention. No adverse events were noted during exercise. QTd decreased significantly in both groups (51 vs 56 ms in MICE, P < 0.05; 34 vs 38 ms in HIIT, P < 0.05). Changes in QTd were correlated with changes in maximal heart rate (r = -0.69, P < 0.0001) and in heart rate recovery (r = -0.49, P < 0.01) in the HIIT group only. When compared to MICE, HIIT training induced a greater decrease in weight, BMI and waist circumference. Exercise capacity significantly improved by 0.82 and 1.25 METs in MICE and HIIT groups respectively (P < 0.0001). Lipid parameters also improved to the same degree in both groups. In MetS, long-term HIIT and MICE training led to comparable effects on ventricular repolarization indices, and HIIT might be associated with greater improvements in certain cardiometabolic risk factors. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Effects of work stress and home stress on autonomic nervous function in Japanese male workers

PubMed Central

MAEDA, Eri; IWATA, Toyoto; MURATA, Katsuyuki

2014-01-01

Autonomic imbalance is one of the important pathways through which psychological stress contributes to cardiovascular diseases/sudden death. Although previous studies have focused mainly on stress at work (work stress), the association between autonomic function and stress at home (home stress) is still poorly understood. The purpose was to clarify the effect of work/home stress on autonomic function in 1,809 Japanese male workers. We measured corrected QT (QTc) interval and QT index on the electrocardiogram along with blood pressure and heart rate. Participants provided self-reported information about the presence/absence of work/home stress and the possible confounders affecting QT indicators. Home stress was related positively to QT index (p=0.040) after adjusting for the possible confounders, though work stress did not show a significant relation to QTc interval or QT index. The odds ratio of home stress to elevated QT index (≥105) was 2.677 (95% CI, 1.050 to 6.822). Work/home stress showed no significant relation to blood pressure or heart rate. These findings suggest that autonomic imbalance, readily assessed by QT indicators, can be induced by home stress in Japanese workers. Additional research is needed to identify different types of home stress that are strongly associated with autonomic imbalance. PMID:25382383

Effects of work stress and home stress on autonomic nervous function in Japanese male workers.

PubMed

Maeda, Eri; Iwata, Toyoto; Murata, Katsuyuki

2015-01-01

Autonomic imbalance is one of the important pathways through which psychological stress contributes to cardiovascular diseases/sudden death. Although previous studies have focused mainly on stress at work (work stress), the association between autonomic function and stress at home (home stress) is still poorly understood. The purpose was to clarify the effect of work/home stress on autonomic function in 1,809 Japanese male workers. We measured corrected QT (QTc) interval and QT index on the electrocardiogram along with blood pressure and heart rate. Participants provided self-reported information about the presence/absence of work/home stress and the possible confounders affecting QT indicators. Home stress was related positively to QT index (p=0.040) after adjusting for the possible confounders, though work stress did not show a significant relation to QTc interval or QT index. The odds ratio of home stress to elevated QT index (≥105) was 2.677 (95% CI, 1.050 to 6.822). Work/home stress showed no significant relation to blood pressure or heart rate. These findings suggest that autonomic imbalance, readily assessed by QT indicators, can be induced by home stress in Japanese workers. Additional research is needed to identify different types of home stress that are strongly associated with autonomic imbalance.

Cardiac repolarization during fingolimod treatment in patients with relapsing-remitting multiple sclerosis.

PubMed

Laiho, Aapo; Laitinen, Tiina M; Hartikainen, Päivi; Hartikainen, Juha E K; Laitinen, Tomi P; Simula, Sakari

2018-02-01

Fingolimod is a sphingosine-1-phosphate receptor modulator for the treatment of relapsing-remitting multiple sclerosis (RRMS). Despite an established effect on heart rate, the effect of fingolimod on cardiac repolarization is not completely known. Twenty-seven patients with RRMS underwent 24-hr ambulatory ECG before fingolimod (baseline), at the day of fingolimod initiation (1D) and after three-month treatment (3M). The mean values of RR-interval as well as QT-interval corrected by Bazzet's (QTcBaz) and Fridericia's (QTcFri) formula were compared between baseline, 1D, and 3M over 24-hr period as well as at daytime and nighttime. QTcBaz over 24-hr was shorter at 1D (414 ± 20 ms, p  < .001) and at 3M (414 ± 20 ms, p  < .001) than at baseline (418 ± 20 ms). In contrast, QTcFri over 24-hr was longer at 1D (410 ± 19 ms, p  < .001) but similar at 3M (406 ± 19 ms, p  = .355) compared to baseline (407 ± 19 ms). Daytime QTcBaz was shorter at 1D ( p  < .001) and at 3M ( p  = .007), whereas daytime QTcFri was longer at 1D ( p  < .05) but similar at 3M ( p  = ns) compared to baseline. During the night, changes were observed neither in QTcBaz nor in QTcFri between baseline, 1D, and 3M. Changes in cardiac repolarization after fingolimod initiation were mild and occurred at daytime. Ambiguously, QTcBaz demonstrated shortening, whereas QTcFri showed prolongation in cardiac repolarization after fingolimod initiation. The formula applied for QT-interval correction needs to be taken carefully into account as evaluating pharmacovigilance issues related to fingolimod.

Dilated cardiomyopathy with short QT interval: is it a new clinical entity?

PubMed

Bohora, Shomu; Namboodiri, Narayanan; Tharakan, Jaganmohan; Vk, Ajit Kumara; Nayyar, Sachin

2009-05-01

Short QT syndrome is a rare autosomal dominant channelopathy of structurally normal hearts characterized by atrial fibrillation, ventricular arrhythmias, and sudden cardiac death. We report a case having short QT, dilated ventricles, and severe ventricular dysfunction, an unreported association so far.

Prevalence of Electrocardiographic Patterns Associated With Sudden Cardiac Death in the Spanish Population Aged 40 Years or Older. Results of the OFRECE Study.

PubMed

Awamleh García, Paula; Alonso Martín, Joaquín Jesús; Graupner Abad, Catherine; Jiménez Hernández, Rosa María; Curcio Ruigómez, Alejandro; Talavera Calle, Pedro; Cristóbal Varela, Carmen; Serrano Antolín, José; Muñiz, Javier; Gómez Doblas, Juan José; Roig, Eulalia

2017-10-01

Some electrocardiographic patterns are associated with an increased risk of sudden cardiac death due to ventricular arrhythmias. There is no information on the prevalence of these patterns in the general population in Spain. The objective of this study was to analyze the prevalence of these patterns and associated clinical and epidemiological factors. This subanalysis of the OFRECE study selected a representative sample of the Spanish population aged ≥ 40 years. We studied the presence or absence of electrocardiographic patterns of Brugada syndrome and QT interval abnormalities. Clinical data and electrocardiograms were available in all participants. Electrocardiograms were evaluated by 2 cardiologists and a third cardiologist was consulted if there was disagreement in the diagnosis. We calculated the weighted prevalence and clinical factors associated with the presence of Brugada-type patterns or QT segment abnormalities. Overall, 8343 individuals were evaluated (59.2 years, 52.4% female). There were 12 Brugada cases (type 1, 2 cases; type 2, 10 cases; weighted prevalence, 0.13%). For corrected QT (QTc) analysis, we excluded participants with left bundle branch block or without sinus rhythm. Weighted prevalences were as follows: short QTc (< 340ms) 0.18%, borderline QTc (441-469ms) 8.33%, long QTc (≥ 470ms criterion) 1.01% and long QTc (≥ 480 criterion) 0.42%. A total of 0.6% to 1.1% of the Spanish population aged ≥ 40 years has an electrocardiographic pattern associated with a higher risk of sudden death (Brugada syndrome, long QT, or short QT). Copyright © 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

The Effects of Fluvoxamine on the Steady-State Plasma Concentrations of Escitalopram and Desmethylescitalopram in Depressed Japanese Patients.

PubMed

Yasui-Furukori, Norio; Tsuchimine, Shoko; Kubo, Kazutoshi; Ishioka, Masamichi; Nakamura, Kazuhiko; Inoue, Yoshimasa

2016-08-01

The aim of this study was to determine the impact of fluvoxamine, an inhibitor of Cytochrome P450 (CYP) 2C19 (CYP2C19), on the pharmacokinetics of escitalopram, a substrate of CYP2C19. Thirteen depressed patients initially received a 20-mg/d dose of escitalopram alone. Subsequently, a 50-mg/d dose of fluvoxamine was administered because of the insufficient efficacy of escitalopram. Plasma concentrations of escitalopram and desmethylescitalopram were quantified using high-performance liquid chromatography before and after fluvoxamine coadministration. The QT and corrected QT (QTc) intervals were measured before and after fluvoxamine coadministration. Fluvoxamine significantly increased the plasma concentrations of escitalopram (72.3 ± 36.9 ng/mL versus 135.2 ± 79.7 ng/mL, P < 0.01) but not those of desmethylescitalopram (21.5 ± 7.0 ng/mL versus 24.9 ± 12.0 ng/mL, no significance [ns]). The ratios of desmethylescitalopram to escitalopram were significantly decreased during fluvoxamine coadministration (0.37 ± 0.21 versus 0.21 ± 0.10, P < 0.01). The CYP2C19 genotype did not fully explain the degree of the change. Fluvoxamine coadministration did not change the QT or QTc intervals. The results of this study suggest that adjunctive treatment with fluvoxamine increases the concentration of escitalopram. The QTc interval did not change in this condition.

An increasing electromechanical window is a predictive marker of ventricular fibrillation in anesthetized rabbit with ischemic heart.

PubMed

Limprasutr, Vudhiporn; Pirintr, Prapawadee; Kijtawornrat, Anusak; Hamlin, Robert L

2018-05-10

The QTc interval is widely used in Safety Pharmacological studies to predict arrhythmia risk, and the electromechanical window (EMW) and short-term variability of QT intervals (STV QT ) have been studied as new biomarkers for drug-induced Torsades de Pointes (TdP). However, the use of EMW and STV QT to predict ventricular fibrillation (VF) has not been elucidated. This study aimed to evaluate EMW and STV QT to predict VF in anesthetized rabbit model of VF. VF was induced by ligation of the left anterior descending and a descending branch of the left circumflex coronary arteries in a sample population of rabbits (n=18). VF was developed 55.6% (10/18). In rabbit with VF, the EMW was significantly higher than in rabbits without VF (96.3 ± 15.6 ms and 49.5 ± 5.6 ms, respectively, P<0.05). STV QT had significantly increased before the onset of VF in rabbits that experienced VF, but not in rabbits that did not experience VF (11.7 ± 1.8 ms and 3.7 ± 0.4 ms, respectively, P<0.05). The EMW and STV QT had better predictive power for VF with higher sensitivity and specificity than the QTc measure. The result suggested that the increasing of EMW, as well as the elevation of STV QT , can potentially be used as biomarkers for predicting of VF.

QT prolongation in the newborn and maternal alcoholism.

PubMed

Krasemann, Thomas

2004-10-01

I discuss a newborn whose mother is addicted to alcohol. On the third day of life, the newborn was found to have ventricular tachycardia. After spontaneous termination of the abnormal rhythm, the duration of the corrected QT interval was 0.48 s. During the next days, the duration of the interval normalized, and has now remained stable for 5 years. I conclude that the so-called "alcohol withdrawal syndrome of the newborn" might cause postnatal prolongation of the QT interval.

Onset of decreased heart work is correlated with increased heart rate and shortened QT interval in high-carbohydrate fed overweight rats.

PubMed

Durak, Aysegul; Olgar, Yusuf; Tuncay, Erkan; Karaomerlioglu, Irem; Kayki Mutlu, Gizem; Arioglu Inan, Ebru; Altan, Vecdi Melih; Turan, Belma

2017-11-01

Mechanical activity of the heart is adversely affected in metabolic syndrome (MetS) characterized by increased body mass and marked insulin resistance. Herein, we examined the effects of high carbohydrate intake on cardiac function abnormalities by evaluating in situ heart work, heart rate, and electrocardiograms (ECGs) in rats. MetS was induced in male Wistar rats by adding 32% sucrose to drinking water for 22-24 weeks and was confirmed by insulin resistance, increased body weight, increased blood glucose and serum insulin, and increased systolic and diastolic blood pressures in addition to significant loss of left ventricular integrity and increased connective tissue around myofibrils. Analysis of in situ ECG recordings showed a markedly shortened QT interval and decreased QRS amplitude with increased heart rate. We also observed increased oxidative stress and decreased antioxidant defense characterized by decreases in serum total thiol level and attenuated paraoxonase and arylesterase activities. Our data indicate that increased heart rate and a shortened QT interval concomitant with higher left ventricular developed pressure in response to β-adrenoreceptor stimulation as a result of less cyclic AMP release could be regarded as a natural compensation mechanism in overweight rats with MetS. In addition to the persistent insulin resistance and obesity associated with MetS, one should consider the decreased heart work, increased heart rate, and shortened QT interval associated with high carbohydrate intake, which may have more deleterious effects on the mammalian heart.

A genome-wide interaction analysis of tri/tetracyclic antidepressants and RR and QT intervals: a pharmacogenomics study from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium

PubMed Central

Noordam, Raymond; Sitlani, Colleen M; Avery, Christy L; Stewart, James D; Gogarten, Stephanie M; Wiggins, Kerri L; Trompet, Stella; Warren, Helen R; Sun, Fangui; Evans, Daniel S; Li, Xiaohui; Li, Jin; Smith, Albert V; Bis, Joshua C; Brody, Jennifer A; Busch, Evan L; Caulfield, Mark J; Chen, Yii-Der I; Cummings, Steven R; Cupples, L Adrienne; Duan, Qing; Franco, Oscar H; Méndez-Giráldez, Rául; Harris, Tamara B; Heckbert, Susan R; van Heemst, Diana; Hofman, Albert; Floyd, James S; Kors, Jan A; Launer, Lenore J; Li, Yun; Li-Gao, Ruifang; Lange, Leslie A; Lin, Henry J; de Mutsert, Renée; Napier, Melanie D; Newton-Cheh, Christopher; Poulter, Neil; Reiner, Alexander P; Rice, Kenneth M; Roach, Jeffrey; Rodriguez, Carlos J; Rosendaal, Frits R; Sattar, Naveed; Sever, Peter; Seyerle, Amanda A; Slagboom, P Eline; Soliman, Elsayed Z; Sotoodehnia, Nona; Stott, David J; Stürmer, Til; Taylor, Kent D; Thornton, Timothy A; Uitterlinden, André G; Wilhelmsen, Kirk C; Wilson, James G; Gudnason, Vilmundur; Jukema, J Wouter; Laurie, Cathy C; Liu, Yongmei; Mook-Kanamori, Dennis O; Munroe, Patricia B; Rotter, Jerome I; Vasan, Ramachandran S; Psaty, Bruce M; Stricker, Bruno H; Whitsel, Eric A

2017-01-01

Background Increased heart rate and a prolonged QT interval are important risk factors for cardiovascular morbidity and mortality, and can be influenced by the use of various medications, including tri/tetracyclic antidepressants (TCAs). We aim to identify genetic loci that modify the association between TCA use and RR and QT intervals. Methods and Results We conducted race/ethnic-specific genome-wide interaction analyses (with HapMap Phase II imputed reference panel imputation) of TCAs and resting RR and QT intervals in cohorts of European (n=45,706; n=1,417 TCA users), African (n=10,235; n=296 TCA users) and Hispanic/Latino (n=13,808; n=147 TCA users) ancestry, adjusted for clinical covariates. Among the populations of European ancestry, two genome-wide significant loci were identified for RR interval: rs6737205 in BRE (β = 56.3, Pinteraction = 3.9e−9) and rs9830388 in UBE2E2 (β = 25.2, Pinteraction = 1.7e−8). In Hispanic/Latino cohorts, rs2291477 in TGFBR3 significantly modified the association between TCAs and QT intervals (β = 9.3, Pinteraction = 2.55e−8). In the meta-analyses of the other ethnicities, these loci either were excluded from the meta-analyses (as part of quality control), or their effects did not reach the level of nominal statistical significance (Pinteraction > 0.05). No new variants were identified in these ethnicities. No additional loci were identified after inverse-variance-weighted meta-analysis of the three ancestries. Conclusion Among Europeans, TCA interactions with variants in BRE and UBE2E2, were identified in relation to RR intervals. Among Hispanic/Latinos, variants in TGFBR3 modified the relation between TCAs and QT intervals. Future studies are required to confirm our results. PMID:28039329

Defective calcium inactivation causes long QT in obese insulin-resistant rat.

PubMed

Lin, Yen-Chang; Huang, Jianying; Kan, Hong; Castranova, Vincent; Frisbee, Jefferson C; Yu, Han-Gang

2012-02-15

The majority of diabetic patients who are overweight or obese die of heart disease. We suspect that the obesity-induced insulin resistance may lead to abnormal cardiac electrophysiology. We tested this hypothesis by studying an obese insulin-resistant rat model, the obese Zucker rat (OZR). Compared with the age-matched control, lean Zucker rat (LZR), OZR of 16-17 wk old exhibited an increase in QTc interval, action potential duration, and cell capacitance. Furthermore, the L-type calcium current (I(CaL)) in OZR exhibited defective inactivation and lost the complete inactivation back to the closed state, leading to increased Ca(2+) influx. The current density of I(CaL) was reduced in OZR, whereas the threshold activation and the current-voltage relationship of I(CaL) were not significantly altered. L-type Ba(2+) current (I(BaL)) in OZR also exhibited defective inactivation, and steady-state inactivation was not significantly altered. However, the current-voltage relationship and activation threshold of I(BaL) in OZR exhibited a depolarized shift compared with LZR. The total and membrane protein expression levels of Cav1.2 [pore-forming subunit of L-type calcium channels (LTCC)], but not the insulin receptors, were decreased in OZR. The insulin receptor was found to be associated with the Cav1.2, which was weakened in OZR. The total protein expression of calmodulin was reduced, but that of Cavβ2 subunit was not altered in OZR. Together, these results suggested that the 16- to 17-wk-old OZR has 1) developed cardiac hypertrophy, 2) exhibited altered electrophysiology manifested by the prolonged QTc interval, 3) increased duration of action potential in isolated ventricular myocytes, 4) defective inactivation of I(CaL) and I(BaL), 5) weakened the association of LTCC with the insulin receptor, and 6) decreased protein expression of Cav1.2 and calmodulin. These results also provided mechanistic insights into a remodeled cardiac electrophysiology under the condition of

The influence of type 2 diabetes and gender on ventricular repolarization dispersion in patients with sub-clinic left ventricular diastolic dysfunction.

PubMed

Jani, Ylber; Kamberi, Ahmet; Xhunga, Sotir; Pocesta, Bekim; Ferati, Fatmir; Lala, Dali; Zeqiri, Agim; Rexhepi, Atila

2015-01-01

To assess the influence of type 2 DM and gender, on the QT dispersion, Tpeak-Tend dispersion of ventricular repolarization, in patients with sub-clinic left ventricular diastolic dysfunction of the heart. QT dispersion, that reflects spatial inhomogeneity in ventricular repolarization, Tpeak-Tend dispersion, this on the other hand reflects transmural inhomogeneity in ventricular repolarization, that is increased in an early stage of cardiomyopathy, and in patients with left ventricular diastolic dysfunction, as well. The left ventricular diastolic dysfunction, a basic characteristic of diabetic heart disease (diabetic cardiomyopathy), that developes earlier than systolic dysfunction, suggests that diastolic markers might be sensitive for early cardiac injury. It is also demonstrated that gender has complex influence on indices of myocardial repolarization abnormalities such as QT interval and QT dispersion. We performed an observational study including 300 diabetic patients with similar epidemiological-demographic characteristics recruited in our institution from May 2009 to July 2014, divided into two groups. Demographic and laboratory echocardiographic data were obtained, twelve lead resting electrocardiography, QT, QTc, Tpeak-Tend-intervals and dispersion, were determined manually, and were compared between various groups. For statistical analysis a t-test, X(2) test, and logistic regression are used according to the type of variables. A p value <0.05 was considered statistically significant for a confidence interval of 95%. QTc max. interval, QTc dispersion and Tpeak-Tend dispersion, were significantly higher in diabetic group with subclinical LV (left ventricular) diastolic dysfunction, than in diabetic group with normal left ventricular diastolic function (445.24±14.7 ms vs. 433.55±14.4 ms, P<0.000; 44.98±18.78 ms vs. 32.05±17.9 ms, P<0.000; 32.60±1.6 ms vs. 17.46±2.0 ms, P<0.02. Prolonged QTc max. interval was found in 33% of patients, indiabetic group

Optimisation of Embryonic and Larval ECG Measurement in Zebrafish for Quantifying the Effect of QT Prolonging Drugs

PubMed Central

Dhillon, Sundeep Singh; Dóró, Éva; Magyary, István; Egginton, Stuart; Sík, Attila; Müller, Ferenc

2013-01-01

Effective chemical compound toxicity screening is of paramount importance for safe cardiac drug development. Using mammals in preliminary screening for detection of cardiac dysfunction by electrocardiography (ECG) is costly and requires a large number of animals. Alternatively, zebrafish embryos can be used as the ECG waveform is similar to mammals, a minimal amount of chemical is necessary for drug testing, while embryos are abundant, inexpensive and represent replacement in animal research with reduced bioethical concerns. We demonstrate here the utility of pre-feeding stage zebrafish larvae in detection of cardiac dysfunction by electrocardiography. We have optimised an ECG recording system by addressing key parameters such as the form of immobilization, recording temperature, electrode positioning and developmental age. Furthermore, analysis of 3 days post fertilization (dpf) zebrafish embryos treated with known QT prolonging drugs such as terfenadine, verapamil and haloperidol led to reproducible detection of QT prolongation as previously shown for adult zebrafish. In addition, calculation of Z-factor scores revealed that the assay was sensitive and specific enough to detect large drug-induced changes in QTc intervals. Thus, the ECG recording system is a useful drug-screening tool to detect alteration to cardiac cycle components and secondary effects such as heart block and arrhythmias in zebrafish larvae before free feeding stage, and thus provides a suitable replacement for mammalian experimentation. PMID:23579446

The role of the Na+/Ca2+ exchanger, INa and ICaL in the genesis of dofetilide-induced torsades de pointes in isolated, AV-blocked rabbit hearts

PubMed Central

Farkas, Attila S; Makra, Péter; Csík, Norbert; Orosz, Szabolcs; Shattock, Michael J; Fülöp, Ferenc; Forster, Tamás; Csanády, Miklós; Papp, Julius Gy; Varró, András; Farkas, András

2009-01-01

Background and purpose: The Na+/Ca2+ exchanger (NCX) may contribute to triggered activity and transmural dispersion of repolarization, which are substrates of torsades de pointes (TdP) type arrhythmias. This study examined the effects of selective inhibition of the NCX by SEA0400 on the occurrence of dofetilide-induced TdP. Experimental approach: Effects of SEA0400 (1 µmol·L−1) on dofetilide-induced TdP was studied in isolated, Langendorff-perfused, atrioventricular (AV)-blocked rabbit hearts. To verify the relevance of the model, lidocaine (30 µmol·L−1) and verapamil (750 nmol·L−1) were also tested against dofetilide-induced TdP. Key results: Acute AV block caused a chaotic idioventricular rhythm and strikingly increased beat-to-beat variability of the RR and QT intervals. SEA0400 exaggerated the dofetilide-induced increase in the heart rate-corrected QT interval (QTc) and did not reduce the incidence of dofetilide-induced TdP [100% in the SEA0400 + dofetilide group vs. 75% in the dofetilide (100 nmol·L−1) control]. In the second set of experiments, verapamil further increased the dofetilide-induced QTc prolongation and neither verapamil nor lidocaine reduced the dofetilide-induced increase in the beat-to-beat variability of the QT interval. However, lidocaine decreased and verapamil prevented the development of dofetilide-induced TdP as compared with the dofetilide control (TdP incidence: 13%, 0% and 88% respectively). Conclusions and implications: Na+/Ca2+ exchanger does not contribute to dofetilide-induced TdP, whereas Na+ and Ca2+ channel activity is involved in TdP genesis in isolated, AV-blocked rabbit hearts. Neither QTc prolongation nor an increase in the beat-to-beat variability of the QT interval is a sufficient prerequisite of TdP genesis in rabbit hearts. PMID:19222480

Mitigating prolonged QT interval in cancer nanodrug development for accelerated clinical translation.

PubMed

Ranjan, Amalendu P; Mukerjee, Anindita; Helson, Lawrence; Vishwanatha, Jamboor K

2013-12-14

Cardiac toxicity is the foremost reason for drug discontinuation from development to clinical evaluation and post market surveillance [Fung 35:293-317, 2001; Piccini 158:317-326 2009]. The Food and Drug Administration (FDA) has rejected many potential pharmaceutical agents due to QT prolongation effects. Since drug development and FDA approval takes an enormous amount of time, money and effort with high failure rates, there is an increased focus on rescuing drugs that cause QT prolongation. If these otherwise safe and potent drugs were formulated in a unique way so as to mitigate the QT prolongation associated with them, these potent drugs may get FDA approval for clinical use. Rescuing these compounds not only benefit the patients who need them but also require much less time and money thus leading to faster clinical translation. In this study, we chose curcumin as our drug of choice since it has been shown to posses anti-tumor properties against various cancers with limited toxicity. The major limitations with this pharmacologically active drug are (a) its ability to prolong QT by inhibiting the hERG channel and (b) its low bioavailability. In our previous studies, we found that lipids have protective actions against hERG channel inhibition and therefore QT prolongation. Results of the manual patch clamp assay of HEK 293 cells clearly illustrated that our hybrid nanocurcumin formulation prevented the curcumin induced inhibition of hERG K+ channel at concentrations higher than the therapeutic concentrations of curcumin. Comparing the percent inhibition, the hybrid nanocurcumin limited inhibition to 24.8% at a high curcumin equivalent concentration of 18 μM. Liposomal curcumin could only decrease this inhibition upto 30% only at lower curcumin concentration of 6 μM but not at 18 μM concentration. Here we show a curcumin encapsulated lipopolymeric hybrid nanoparticle formulation which could protect against QT prolongation and also render increased

QT Prolongation, Torsades de Pointes, and Psychotropic Medications: A 5-Year Update.

PubMed

Beach, Scott R; Celano, Christopher M; Sugrue, Alan M; Adams, Caitlin; Ackerman, Michael J; Noseworthy, Peter A; Huffman, Jeff C

Some psychotropic medications have been associated with prolongation of the QT interval and QT prolongation, especially in those with medical illness, and are linked to lethal ventricular arrhythmias, such as Torsades de Pointes (TdP). In 2013, we published a review of QT prolongation, TdP, and psychotropic medications. We provide an update over the past 5 years on the specific concerns most relevant to clinicians who see medically ill patients. In this nonsystematic review, we aimed to carefully and intensively identify new articles by utilizing a structured PubMed search from 2012-present. QT prolongation remains an imperfect, though well-established marker of risk for TdP. Among antidepressant medications, citalopram does appear to prolong the QT interval more than other selective serotonin reuptake inhibitors, though the clinical significance of this prolongation remains unclear. Escitalopram appears to prolong the QT interval to a lesser extent. Haloperidol carries a risk for QT prolongation, but the assertion that intravenous haloperidol is inherently riskier may be confounded by its primary use in medically ill populations. Among atypical antipsychotic agents, ziprasidone-and possibly iloperidone-is associated with the greatest QT prolongation, whereas aripiprazole appears safest from this standpoint. The evidence for clinically meaningful QT prolongation with most classes of psychiatric agents remains minimal. The most important risk-reducing intervention clinicians can make is undertaking a careful analysis of other QT risk factors when prescribing psychiatric medications. Copyright © 2017 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.

Evaluation of 5 Hour Energy Drink on the Blood Pressure and Electrocardiograph Parameters on Young Healthy Volunteers: A Randomized, Double Blind, Crossover, Placebo-Controlled Trial (Presentation)

DTIC Science & Technology

2014-02-11

other substances. • There have been reports of atrial fibrillation , Takotsubo cardiomyopathy and sudden cardiac deaths in healthy individuals...baseline cardiac rhythm, history of atrial or ventricular arrhythmia, baseline corrected QT (QTc) interval greater than 440 milliseconds (msec

Evaluation of electrocardiographic parameters for early diagnosis of autonomic dysfunction in children and adolescents with type-1 diabetes mellitus.

PubMed

Uysal, Fahrettin; Ozboyaci, Evren; Bostan, Ozlem; Saglam, Halil; Semizel, Evren; Cil, Ergun

2014-10-01

The aim of this study was to identify the sensitivity of electrocardiogram (ECG) in early diagnosis of cardiac autonomic function disorder in children with type 1 diabetes mellitus. A total of 150 children and adolescents with type 1 diabetes mellitus were enrolled between June 2009 and June 2010, as well as 100 age- and sex-matched healthy control children. Twelve-lead ECG was done in all cases and heart rate, QT and QTc interval, dispersion of P wave (Pd), and of QT (QTd) and QTc interval (QTcd) were measured. The clinical and demographic features such as age, gender, duration of follow up and level of HbA1c and fasting glucose were obtained and the effects of these parameters on ECG measurements were investigated. The mean age of the patients and controls was 11.61 ± 3.72 years and 10.92 ± 3.2 years, respectively. QT and QTc interval and QTcd interval were significantly higher in diabetic children compared to healthy controls but these ECG findings were not associated with the duration of diabetes or glycemic state. Pd was significantly higher in the diabetic patients with HbA1c >7.5% compared to control, and this was also found in patients that were followed up >1 year. Cardiac autonomic function disorder, which is one of the most important causes of morbidity and mortality, may emerge in the course of type 1 diabetes mellitus. It can be diagnosed on ECG even when the patients are asymptomatic. © 2014 Japan Pediatric Society.

In vivo effects of the IKr agonist NS3623 on cardiac electrophysiology of the guinea pig.

PubMed

Hansen, Rie Schultz; Olesen, Søren-Peter; Rønn, Lars Christian B; Grunnet, Morten

2008-07-01

The long QT syndrome is characterized by a prolongation of the QT interval measured on the surface electrocardiogram. Prolonging the QT interval increases the risk of dangerous ventricular fibrillations, eventually leading to sudden cardiac death. Pharmacologically induced QT interval prolongations are most often caused by antagonizing effects on the repolarizing cardiac current called IKr. In humans IKr is mediated by the human ether-a-go-go related gene (hERG) potassium channel. We recently presented NS3623, a compound that selectively activates this channel. The present study was dedicated to examining the in vivo effects of NS3623. Injection of 30 mg/kg NS3623 shortened the corrected QT interval by 25 +/- 4% in anaesthetized guinea pigs. Accordingly, 50 mg/kg of NS3623 shortened the QT interval by 30 +/- 6% in conscious guinea pigs. Finally, pharmacologically induced QT prolongation by a hERG channel antagonist (0.15 mg/kg E-4031) could be reverted by injection of NS3623 (50 mg/kg) in conscious guinea pigs. In conclusion, the present in vivo study demonstrates that injection of the hERG channel agonist NS3623 results in shortening of the QTc interval as well as reversal of a pharmacologically induced QT prolongation in both anaesthetized and conscious guinea pigs.

Methadone, QTc prolongation and torsades de pointes: Current concepts, management and a hidden twist in the tale?

PubMed

Mujtaba, Sobia; Romero, Jorge; Taub, Cynthia C

2013-12-01

Methadone is a drug that has found widespread utility in the management of opioid addiction and pain. Along with its popularity, methadone has also earned an infamous reputation for causing prolongation of the QT interval and an increased risk of torsades de pointes. In this article we will give a brief overview of the long QT syndromes, followed by an in-depth look at the current pathophysiologic mechanisms of methadone induced QT prolongation, a review of the existing literature and the current concepts regarding the prevention and management of methadone induced torsades de pointes. In addition, we explore the idea and implications of a genetic link between methadone induced prolongation of the QT interval and torsades de pointes.

Ventricular Effective Refraction Period and Ventricular Repolarization Analysis in Experimental Tachycardiomyopathy in Swine.

PubMed

Noszczyk-Nowak, Agnieszka; Pasławska, Urszula; Gajek, Jacek; Janiszewski, Adrian; Pasławski, Robert; Zyśko, Dorota; Nicpoń, Józef

2016-01-01

Swine are recognized animal models of human cardiovascular diseases. However, little is known on the CHF-associated changes in the electrophysiological ventricular parameters of humans and animals. The aim of this study was to analyze changes in the durations of ventricular effective refraction period (VERP), QT and QTc intervals of pigs with chronic tachycardia-induced tachycardiomyopathy (TIC). The study was comprised of 28 adult pigs (8 females and 20 males) of the Polish Large White breed. A one-chamber pacemaker was implanted in each of the 28 pigs. Electrocardiographic, echocardiographic and electrophysiological studies were carried out prior to the pacemaker implantation and at subsequent 4-week intervals. All electrocardiographic, echocardiographic and short electrophysiological study measurements in all swine were done under general anesthesia (propofol) after premedication with midazolam, medetomidine, and ketamine. No significant changes in the duration of QT interval and corrected QT interval (QTc) were observed during consecutive weeks of the experiment. The duration of the QTc interval of female pigs was shown to be significantly longer than that of the males throughout the whole study period. Beginning from the 12th week of rapid ventricular pacing, a significant increase in duration of VERP was observed in both male and female pigs. Males and females did not differ significantly in terms of VERP duration determined throughout the whole study period. Ventricular pacing, stimulation with 2 and 3 premature impulses at progressively shorter coupling intervals and an imposed rhythm of 130 bpm or 150 bpm induced transient ventricular tachycardia in one female pig and four male pigs. One episode of permanent ventricular tachycardia was observed. The number of induced arrhythmias increased proportionally to the severity of heart failure and duration of the experiment. However, relatively aggressive protocols of stimulation were required in order to induce

Patients With Long-QT Syndrome Caused by Impaired hERG-Encoded Kv11.1 Potassium Channel Have Exaggerated Endocrine Pancreatic and Incretin Function Associated With Reactive Hypoglycemia

PubMed Central

Hyltén-Cavallius, Louise; Iepsen, Eva W.; Wewer Albrechtsen, Nicolai J.; Svendstrup, Mathilde; Lubberding, Anniek F.; Hartmann, Bolette; Jespersen, Thomas; Linneberg, Allan; Christiansen, Michael; Vestergaard, Henrik; Pedersen, Oluf; Holst, Jens J.; Kanters, Jørgen K.

2017-01-01

, and small interfering RNA inhibition of hERG in β and L cells increased insulin and GLP-1 secretion up to 50%. Glucose ingestion caused cardiac repolarization disturbances with increased QTc intervals in both patients and controls, but with a 122% greater increase in QTcF interval in LQT2 patients (P=0.004). Conclusions: Besides a prolonged cardiac repolarization phase, LQT2 patients display increased GLP-1, GIP, and insulin secretion and defective glucagon secretion, causing decreased plasma glucose and thus increased risk of hypoglycemia. Furthermore, glucose ingestion increased QT interval and aggravated the cardiac repolarization disturbances in LQT2 patients. Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT02775513. PMID:28235848

The assessment of P-wave dispersion and myocardial repolarization parameters in patients with chronic kidney disease.

PubMed

Kollu, Korhan; Altintepe, Lutfullah; Duran, Cevdet; Topal, Mustafa; Ecirli, Samil

2018-11-01

The risks of sudden death and cardiac arrhythmia are increased in patients with chronic kidney disease (CKD). Here, we aimed to evaluate the indicators of arrhythmias, such as p-wave dispersion (P-WD), QTc dispersion, Tp-e and Tp-e/QT ratio in patients with CKD stages 3-5 on no renal replacement therapy (RRT). One-hundred and thirty three patients with CKD stages 3-5 and 32 healthy controls were enrolled into the study. No patients received RRT. QTc dispersion, P-WD and Tp-e interval were measured using electrocardiogram and Tp-e/QT ratio was also calculated. Mean age rates were found similar in patients and controls (60.8 ± 14.2 and 61 ± 12.9 y, p = .937, respectively). Compared patients with controls, P-WD (45.85 ± 12.42 vs. 21.17 ± 6.6 msec, p < .001), QTc-min (366.99 ± 42.31 vs. 387.15 ± 20.5 msec, p < .001), QTc dispersion (71.13 ± 27.95 vs. 41.25 ± 14.55 msec, p < .001), Tp-e maximum (81.04 ± 10.34 vs. 75.49 ± 10.9 msec, p < .001), Tp-e minimum (62.25 ± 7.58 vs. 54.8 ± 6.72 msec, p < .001) and Tp-e/QTc ratio (0.19 ± 0.02 vs. 0.18 ± 0.01, p = .001) were found to be different. QTc-max and Tp-e interval were found to be similar in both groups. P-WD and QTc dispersion, Tp-e interval and Tp-e/QTc ratio were found to be increased in with CKD stages 3-5 on no RRT.

Early changes in myocardial repolarization and coronary perfusion after cardiopulmonary bypass surgery for ASD repair in children.

PubMed

Aburawi, Elhadi H; Souid, Abdul-Kader; Liuba, Petru; Zoubeidi, Taoufik; Pesonen, Erkki

2013-09-10

In adults, impaired myocardial repolarization and increased risk of arrhythmia are known consequences of open heart surgery. Little is known, however, about post-operative consequences of cardiopulmonary bypass surgery in children. The aim of this study was to assess ventricular repolarization and coronary perfusion after bypass surgery for atrial septal defect (ASD) repair in children. Twelve patients with ASD were assessed one day before and 5-6 days after ASD repair. Myocardial repolarization (corrected QT interval, QTc, QT dispersion, QTd, and PQ interval) was determined on 12-lead electrocardiograms. Coronary flow in proximal left anterior descending artery (peak flow velocity in diastole, PFVd) was assessed by transthoracic Doppler echocardiography. Ten of the 12 (83%) children had normal myocardial repolarization before and after surgery. After surgery, QTc increased 1-9% in 5 (42%) patients, decreased 2-11% in 5 (42%) patients and did not change in 2 (16%) patients. Post-op QTc positively correlated with bypass time (R=0.686, p=0.014) and changes in PFVd (R=0.741, p=0.006). After surgery, QTd increased 33-67% in 4 (33%) patients, decreased 25-50% in 6 patients (50%) and did not change in 2 (16%) patients. After surgery, PQ interval increased 5-30% in 4 (33%) patients, decreased 4-29% in 6 (50%) patients and did not change in 1 (8%) patient. Post-op PQ positively correlated with bypass time (R=0.636, p=0.027). As previously reported, PFVd significantly increased after surgery (p<0.001). Changes in QTc, PQ and PFVd are common in young children undergoing surgery for ASD repair. Post-op QTc significantly correlates with bypass time, suggesting prolonged cardiopulmonary bypass may impair ventricular repolarization. Post-op QTc significantly correlates with PFVd changes, suggesting increased coronary flow may also impair ventricular repolarization. The clinical significance and reversibility of these alternations require further investigations.

Methadone, QTc prolongation and torsades de pointes: Current concepts, management and a hidden twist in the tale?

PubMed Central

Mujtaba, Sobia; Romero, Jorge; Taub, Cynthia C.

2013-01-01

Methadone is a drug that has found widespread utility in the management of opioid addiction and pain. Along with its popularity, methadone has also earned an infamous reputation for causing prolongation of the QT interval and an increased risk of torsades de pointes. In this article we will give a brief overview of the long QT syndromes, followed by an in-depth look at the current pathophysiologic mechanisms of methadone induced QT prolongation, a review of the existing literature and the current concepts regarding the prevention and management of methadone induced torsades de pointes. In addition, we explore the idea and implications of a genetic link between methadone induced prolongation of the QT interval and torsades de pointes. PMID:24653586

Acute effects of Red Bull energy drink on ventricular repolarization in healthy young volunteers: a prospective study

PubMed Central

Elitok, Ali; Öz, Fahrettin; Panc, Cafer; Sarıkaya, Remzi; Sezikli, Selim; Pala, Yasin; Bugan, Övgü Sinem; Ateş, Müge; Parıldar, Hilal; Ayaz, Mustafa Buğra; Atıcı, Adem; Oflaz, Hüseyin

2016-01-01

Objective: Energy drinks (EDs) are widely consumed products of the beverage industry and are often chosen by teenagers and young adults. Several adverse cardiovascular events and malignant cardiac arrhythmias following consumption of EDs have been reported in the literature. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the dispersion of repolarization and that an increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. This study investigated the acute effects of Red Bull ED on ventricular repolarization as assessed by the Tp-e interval and Tp-e/QT ratio. Methods: A prospective, open-label study design was used. After an 8-h fast, 50 young, healthy subjects consumed 355 mL of Red Bull ED. The Tp-e interval, Tp-e/QTc ratio, and several other electrocardiographic parameters were measured at baseline and 2 h after ingestion of Red Bull ED. Results: No significant changes in the Tp-e interval or Tp-e/QTc ratio were observed with Red Bull ED consumption. Red Bull ED consumption led to increases in both systolic and diastolic blood pressures, which were associated with an increased heart rate. Conclusion: Although ingestion of Red Bull ED increases the heart rate and diastolic and systolic blood pressures, it does not cause alterations in ventricular repolarization as assessed by the Tp-e interval and Tp-e/QTc ratio. PMID:25868042

Acute effects of Red Bull energy drink on ventricular repolarization in healthy young volunteers: a prospective study.

PubMed

Elitok, Ali; Öz, Fahrettin; Panc, Cafer; Sarıkaya, Remzi; Sezikli, Selim; Pala, Yasin; Bugan, Övgü Sinem; Ateş, Müge; Parıldar, Hilal; Ayaz, Mustafa Buğra; Atıcı, Adem; Oflaz, Hüseyin

2015-11-01

Energy drinks (EDs) are widely consumed products of the beverage industry and are often chosen by teenagers and young adults. Several adverse cardiovascular events and malignant cardiac arrhythmias following consumption of EDs have been reported in the literature. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the dispersion of repolarization and that an increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. This study investigated the acute effects of Red Bull ED on ventricular repolarization as assessed by the Tp-e interval and Tp-e/QT ratio. A prospective, open-label study design was used. After an 8-h fast, 50 young, healthy subjects consumed 355 mL of Red Bull ED. The Tp-e interval, Tp-e/QTc ratio, and several other electrocardiographic parameters were measured at baseline and 2 h after ingestion of Red Bull ED. No significant changes in the Tp-e interval or Tp-e/QTc ratio were observed with Red Bull ED consumption. Red Bull ED consumption led to increases in both systolic and diastolic blood pressures, which were associated with an increased heart rate. Although ingestion of Red Bull ED increases the heart rate and diastolic and systolic blood pressures, it does not cause alterations in ventricular repolarization as assessed by the Tp-e interval and Tp-e/QTc ratio.

Why are we prolonging QT interval monitoring?

PubMed

Barrett, Trina

2015-01-01

At present, monitoring of the QT interval (QTI) is not a standard practice in the medical intensive care unit setting, where many drugs that prolong the QTI are administered. This literature review looked at the current research for evidence-based standards to support QTI monitoring of patients with risk factors for QTI prolongation, which can result in life-threatening arrhythmias such as torsade de pointes. The objective of this article is to establish the existence of evidence-based standards for monitoring of the QTI and to raise awareness in the nursing profession of the need for such monitoring among patients who are at high risk for prolonged QTI. To determine whether published standards for QTI monitoring exist, a search was conducted of the bibliographic databases CINAHL, EBSCOhost, Medline, PubMed, Google Scholar, and the Cochrane Library for the years 2013 and 2014. Also, a survey was conducted to determine whether practice standards for QTI monitoring are being implemented at 4 major hospitals in the Memphis area, including a level 1 trauma center. The database search established the existence of published guidelines that support the need for QTI monitoring. Results of the hospital survey indicated that direct care nurses were not aware of the need to identify high-risk patients, drugs with the potential to prolong QTI that were being administered to their patients, or evidence-based standards for QTI monitoring. Review of the research literature underscored the need for QTI monitoring among high-risk patients, that is, those with genetic conditions that predispose them to QTI prolongation, those with existing cardiac conditions being treated with antiarrhythmic medications, or those who are prescribed any new medication classified as high risk on the basis of clinical research. This need is especially crucial in intensive care unit settings, where many antiarrhythmic medications are administered.

A single-dose, crossover, placebo- and moxifloxacin-controlled study to assess the effects of neratinib (HKI-272) on cardiac repolarization in healthy adult subjects.

PubMed

Hug, Bruce; Abbas, Richat; Leister, Cathie; Burns, Jaime; Sonnichsen, Daryl

2010-08-01

Neratinib is an orally administered, small-molecule, irreversible pan-ErbB inhibitor in development for the treatment of ErbB2-positive breast cancer. This study assessed the effects of therapeutic and supratherapeutic neratinib concentrations on cardiac repolarization, in accordance with current regulatory guidance. This was a two-part study in healthy subjects. In part 1, subjects were randomized to receive placebo, 400 mg moxifloxacin, or 240 mg neratinib (therapeutic dose) following a high-fat meal. In part 2, after a washout period, subjects received placebo plus 400 mg ketoconazole or 240 mg neratinib plus ketoconazole (supratherapeutic dose). ANOVA was used to compare the baseline-adjusted QTc interval for neratinib with that of placebo (reference), and for neratinib plus ketoconazole with that of placebo plus ketoconazole (reference). Pharmacokinetic/pharmacodynamic analyses and categorical summaries of interval data were done. Assay sensitivity was evaluated by the effect of moxifloxacin on QTc compared with placebo. Sixty healthy subjects were enrolled in this study. The upper bounds of the 90% confidence interval for baseline-adjusted QTcN (population-specific corrected QT) were QTc interval. No subjects had QTcI, QTcF, or QTcN intervals >450 milliseconds or change from baseline >30 milliseconds. Moxifloxacin produced a significant increase in QTcN compared with placebo (P < 0.05). Therapeutic and supratherapeutic plasma concentrations of neratinib do not prolong the QTc interval in healthy subjects. (c) 2010 AACR.

Long QT syndrome unmasked in an adult subject presenting with excited delirium.

PubMed

Bozeman, William P; Ali, Karim; Winslow, James E

2013-02-01

Excited delirium is increasingly recognized as a risk factor for sudden death, though the specific pathophysiology of these deaths is typically unclear. We describe a survivor of excited delirium that displayed a transient severe prolongation of the QT interval, suggesting unmasking of long QT syndrome as a possible mechanism of sudden death. A 30-year-old man was arrested by police for violent assaultive behavior. Officers at the scene noted confusion, nonsensical speech, sweating, and bizarre agitated behavior; he was transported to the Emergency Department for medical evaluation of possible excited delirium. His initial electrocardiogram revealed a markedly prolonged corrected QT interval of over 600 ms. Intravenous hydration and sodium bicarbonate were administered, with normalization of the QT; he was admitted and recovered uneventfully. We discuss the possible association between long QT syndrome and unexplained sudden deaths seen with excited delirium. Sodium bicarbonate may be considered when long QT syndrome is identified during or after agitated delirium, though its routine use cannot be recommended based on a case report. Copyright © 2013 Elsevier Inc. All rights reserved.

Epilepsy is associated with ventricular alterations following convulsive status epilepticus in children.

PubMed

Ali, Wail; Bubolz, Beth A; Nguyen, Linh; Castro, Danny; Coss-Bu, Jorge; Quach, Michael M; Kennedy, Curtis E; Anderson, Anne E; Lai, Yi-Chen

2017-12-01

Convulsive status epilepticus can exert profound cardiovascular effects in adults including ventricular depolarization-repolarization abnormalities. Whether status epilepticus adversely affects ventricular electrical properties in children is less understood. Therefore, we sought to characterize ventricular alterations and the associated clinical factors in children following convulsive status epilepticus. We conducted a 2-year retrospective, case-control study. Children between 1 month and 21 years of age were included if they were admitted to the pediatric intensive care unit with primary diagnosis of convulsive status epilepticus and had 12-lead electrocardiogram (ECG) within 24 hours of admission. Children with heart disease, ion channelopathy, or on vasoactive medications were excluded. Age-matched control subjects had no history of seizures or epilepsy. The primary outcome was ventricular abnormalities represented by ST segment changes, abnormal T wave, QRS axis deviation, and corrected QT (QTc) interval prolongation. The secondary outcomes included QT/RR relationship, beat-to-beat QTc interval variability, ECG interval measurement between groups, and clinical factors associated with ECG abnormalities. Of 317 eligible children, 59 met the inclusion criteria. History of epilepsy was present in 31 children (epileptic) and absent in 28 children (non-epileptic). Compared with the control subjects (n = 31), the status epilepticus groups were more likely to have an abnormal ECG with overall odds ratio of 3.8 and 7.0 for the non-epileptic and the epileptic groups respectively. Simple linear regression analysis demonstrated that children with epilepsy exhibited impaired dependence and adaptation of the QT interval on heart rate. Beat-to-beat QTc interval variability, a marker of ventricular repolarization instability, was increased in children with epilepsy. Convulsive status epilepticus can adversely affect ventricular electrical properties and stability in children

Risk management of QTc-prolongation in patients receiving haloperidol: an epidemiological study in a University hospital in Belgium.

PubMed

Vandael, Eline; Vandenberk, Bert; Vandenberghe, Joris; Spriet, Isabel; Willems, Rik; Foulon, Veerle

2016-04-01

Many drugs, including haloperidol, are linked with a risk of QTc-prolongation, which can lead to Torsade de Pointes and sudden cardiac death. To investigate the prevalence of concomitant risk factors for QTc-prolongation in patients treated with haloperidol, and the use of safety measures to minimize this risk. University Hospitals of Leuven, Belgium. Methods A retrospective epidemiological study was performed. On 15 consecutive Mondays, all patients with a prescription for haloperidol were included. A risk score for QTc-prolongation, inspired by the pro-QTc score of Haugaa et al., was calculated based on gender, comorbidities, lab results and concomitant QTc-prolonging drugs (each factor counting for one point). Available electrocardiograms before and during the treatment of haloperidol were registered. Management of the risk of QTc-prolongation. Two hundred twenty-two patients were included (59.0 % men, median age 77 years) of whom 26.6 % had a risk score of ≥4 (known to significantly increase the mortality). Overall, 24.3 % received haloperidol in combination with other drugs with a known risk of Torsade de Pointes. Half of the patients had an electrocardiogram in the week before the start of haloperidol; only in one-third a follow-up electrocardiogram during haloperidol treatment was performed. Of the patients with a moderately (n = 41) or severely (n = 14) prolonged QTc-interval before haloperidol, 48.8 % and 42.9 % respectively had a follow-up electrocardiogram. In patients with a risk score ≥4, significantly more electrocardiograms were taken before starting haloperidol (p = 0.020). Although many patients had risk factors for QTc-prolongation (including the use of other QTc-prolonging drugs) or had a prolonged QTc on a baseline electrocardiogram, follow-up safety measures were limited. Persistent efforts should be taken to develop decision support systems to manage this risk.

Beyond the Length and Look of Repolarization: Defining the Non-QTc Electrocardiographic Profiles of Patients with Congenital Long QT Syndrome.

PubMed

Lane, Conor M; Bos, J Martijn; Rohatgi, Ram K; Ackerman, Michael J

2018-04-30

Little is known about the spectrum and prevalence of ECG features beyond the length and morphology of repolarization in patients with congenital long QT syndrome (LQTS). To characterize the full ECG phenotype of LQTS patients and evaluate differences by age and LQTS genotype. Retrospective review of 943 patients with LQTS (57% female, median age 25 years; IQR 9 - 34 years) was performed. Comprehensive analysis of their initial evaluation ECG was performed using definitions outlined in Heart Rhythm Society guidelines. Bradycardia was common (n=320; 34%), regardless of beta-blocker use. Left axis deviation (n=33, 3.5%) and bundle branch block (n=5, 0.5%) were uncommon. T-wave inversion (TWI) involving leads V1 and V3 was more common in LQT2 compared to LQT1 or LQT3 [OR for V1: 2.67 (95% CI 1.8 - 3.9) and OR for V3: 1.76 (95% CI 1.2 - 2.6)], while TWI in lead III and aVF was most common in LQT3 [OR for III: 2.38 (95% CI 1.4 - 4.2) and OR for aVF: 3.14 (95% CI 1.6 - 6.4)]. Notched T-waves were most apparent at younger ages (48% in patients between ages 4-10 compared to 12% in over 40s, p <0.0001). Beyond the QT interval and bradycardia, ECG abnormalities are uncommon in LQTS patients and patients almost never have concomitant bundle branch block. Notably, 19% of LQTS patients overall and 27% of LQT2 patients exhibit anterior TWI that would satisfy a diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy creating the potential for diagnostic miscues. Copyright © 2018. Published by Elsevier Inc.

P-wave and QT dispersion in patients with conversion disorder.

PubMed

Izci, Filiz; Hocagil, Hilal; Izci, Servet; Izci, Vedat; Koc, Merve Iris; Acar, Rezzan Deniz

2015-01-01

The aim of this study was to investigate QT dispersion (QTd), which is the noninvasive marker of ventricular arrhythmia and sudden cardiac death, and P-wave dispersion, which is the noninvasive marker of atrial arrhythmia, in patients with conversion disorder (CD). A total of 60 patients with no known organic disease who were admitted to outpatient emergency clinic and were diagnosed with CD after psychiatric consultation were included in this study along with 60 healthy control subjects. Beck Anxiety Inventory and Beck Depression Scale were administered to patients and 12-lead electrocardiogram measurements were obtained. Pd and QTd were calculated by a single blinded cardiologist. There was no statistically significant difference in terms of age, sex, education level, socioeconomic status, weight, height, and body mass index between CD patients and controls. Beck Anxiety Inventory scores (25.2±10.8 and 3.8±3.2, respectively, P<0.001) and Beck Depression Scale scores (11.24±6.15 and 6.58±5.69, respectively, P<0.01) were significantly higher in CD patients. P-wave dispersion measurements did not show any significant differences between conversion patients and control group (46±5.7 vs 44±5.5, respectively, P=0.156). Regarding QTc and QTd, there was a statistically significant increase in all intervals in conversion patients (416±10 vs 398±12, P<0.001, and 47±4.8 vs 20±6.1, P<0.001, respectively). A similar relation to that in literature between QTd and anxiety and somatoform disorders was also observed in CD patients. QTc and QTd were significantly increased compared to the control group in patients with CD. These results suggest a possibility of increased risk of ventricular arrhythmia resulting from QTd in CD patients. Larger samples are needed to evaluate the clinical course and prognosis in terms of arrhythmia risk in CD patients.

The influence of type 2 diabetes and gender on ventricular repolarization dispersion in patients with sub-clinic left ventricular diastolic dysfunction

PubMed Central

Jani, Ylber; Kamberi, Ahmet; Xhunga, Sotir; Pocesta, Bekim; Ferati, Fatmir; Lala, Dali; Zeqiri, Agim; Rexhepi, Atila

2015-01-01

Objective: To assess the influence of type 2 DM and gender, on the QT dispersion, Tpeak-Tend dispersion of ventricular repolarization, in patients with sub-clinic left ventricular diastolic dysfunction of the heart. Background: QT dispersion, that reflects spatial inhomogeneity in ventricular repolarization, Tpeak-Tend dispersion, this on the other hand reflects transmural inhomogeneity in ventricular repolarization, that is increased in an early stage of cardiomyopathy, and in patients with left ventricular diastolic dysfunction, as well. The left ventricular diastolic dysfunction, a basic characteristic of diabetic heart disease (diabetic cardiomyopathy), that developes earlier than systolic dysfunction, suggests that diastolic markers might be sensitive for early cardiac injury. It is also demonstrated that gender has complex influence on indices of myocardial repolarization abnormalities such as QT interval and QT dispersion. Material and methods: We performed an observational study including 300 diabetic patients with similar epidemiological-demographic characteristics recruited in our institution from May 2009 to July 2014, divided into two groups. Demographic and laboratory echocardiographic data were obtained, twelve lead resting electrocardiography, QT, QTc, Tpeak-Tend-intervals and dispersion, were determined manually, and were compared between various groups. For statistical analysis a t-test, X2 test, and logistic regression are used according to the type of variables. A p value <0.05 was considered statistically significant for a confidence interval of 95%. Results: QTc max. interval, QTc dispersion and Tpeak-Tend dispersion, were significantly higher in diabetic group with subclinical LV (left ventricular) diastolic dysfunction, than in diabetic group with normal left ventricular diastolic function (445.24±14.7 ms vs. 433.55±14.4 ms, P<0.000; 44.98±18.78 ms vs. 32.05±17.9 ms, P<0.000; 32.60±1.6 ms vs. 17.46±2.0 ms, P<0.02. Prolonged QTc max

Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model

PubMed Central

Yao, X; Anderson, D L; Ross, S A; Lang, D G; Desai, B Z; Cooper, D C; Wheelan, P; McIntyre, M S; Bergquist, M L; MacKenzie, K I; Becherer, J D; Hashim, M A

2008-01-01

Background and purpose: Drug-induced prolongation of the QT interval can lead to torsade de pointes, a life-threatening ventricular arrhythmia. Finding appropriate assays from among the plethora of options available to predict reliably this serious adverse effect in humans remains a challenging issue for the discovery and development of drugs. The purpose of the present study was to develop and verify a reliable and relatively simple approach for assessing, during preclinical development, the propensity of drugs to prolong the QT interval in humans. Experimental approach: Sixteen marketed drugs from various pharmacological classes with a known incidence—or lack thereof—of QT prolongation in humans were examined in hERG (human ether a-go-go-related gene) patch-clamp assay and an anaesthetized guinea-pig assay for QT prolongation using specific protocols. Drug concentrations in perfusates from hERG assays and plasma samples from guinea-pigs were determined using liquid chromatography-mass spectrometry. Key results: Various pharmacological agents that inhibit hERG currents prolong the QT interval in anaesthetized guinea-pigs in a manner similar to that seen in humans and at comparable drug exposures. Several compounds not associated with QT prolongation in humans failed to prolong the QT interval in this model. Conclusions and implications: Analysis of hERG inhibitory potency in conjunction with drug exposures and QT interval measurements in anaesthetized guinea-pigs can reliably predict, during preclinical drug development, the risk of human QT prolongation. A strategy is proposed for mitigating the risk of QT prolongation of new chemical entities during early lead optimization. PMID:18587422

Acotiamide hydrochloride (Z-338), a new selective acetylcholinesterase inhibitor, enhances gastric motility without prolonging QT interval in dogs: comparison with cisapride, itopride, and mosapride.

PubMed

Matsunaga, Yugo; Tanaka, Takao; Yoshinaga, Koji; Ueki, Shigeru; Hori, Yuko; Eta, Runa; Kawabata, Yoshihiro; Yoshii, Kazuyoshi; Yoshida, Kenji; Matsumura, Toshihiro; Furuta, Shigeru; Takei, Mineo; Tack, Jan; Itoh, Zen

2011-03-01

Acotiamide hydrochloride (acotiamide; N-[2-[bis(1-methylethyl) amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl) amino] thiazole-4-carboxamide monohydrochloride trihydrate, Z-338) has been reported to improve meal-related symptoms of functional dyspepsia in clinical studies. Here, we examined the gastroprokinetic effects of acotiamide and its antiacetylcholinesterase activity as a possible mechanism of action in conscious dogs. Acotiamide increased postprandial gastric motor activity in conscious dogs with chronically implanted force transducers and, like itopride, mosapride, and cisapride, exhibited gastroprokinetic activity in these dogs. Furthermore, acotiamide improved clonidine-induced hypomotility and delayed gastric emptying. Acotiamide-enhanced postprandial gastroduodenal motility was suppressed completely by pretreatment with atropine, a muscarinic receptor antagonist. In in vitro studies, acotiamide enhanced acetylcholine- but not carbachol-induced contractile responses of guinea pig gastric antrum strips. Moreover, like itopride and neostigmine, acotiamide inhibited recombinant human and canine stomach-derived acetylcholinesterase (AChE) activity in vitro. The mode of the AChE inhibitory action of acotiamide was selective and reversible. Unlike itopride or mosapride, acotiamide showed no affinity for dopamine D(2) or serotonin 5-HT(4) receptors. With regard to cardiovascular side effects, unlike cisapride, acotiamide did not affect myocardial monophasic action potential duration, QT interval, or corrected QT interval in anesthetized dogs. These results suggest that acotiamide stimulates gastric motility in vivo by inhibiting AChE activity without affecting QT interval. Acotiamide thus represents a beneficial new drug for the treatment of functional dyspepsia involving gastric motility dysfunction, with differences from other prokinetic agents.

Sports Participation in Genotype Positive Children With Long QT Syndrome

PubMed Central

Aziz, Peter F.; Sweeten, Tammy; Vogel, Ramon L.; Bonney, William J.; Henderson, Jacqueline; Patel, Akash R.; Shah, Maully J.

2015-01-01

OBJECTIVE The study sought to examine the prevalence and outcomes of sports participation (both competitive and recreational) in our single-center LQTS genotype positive pediatric population. BACKGROUND The risks of sports participation in patients with long QT syndrome (LQTS) are not clearly elucidated. METHODS A retrospective review was performed on genotype positive patients referred for the evaluation and management of LQTS between 1998 and 2013 at the Children’s Hospital of Philadelphia. Pediatric patients participating in competitive or recreational sports were included in the analysis and their charts were reviewed for documented LQTS events during follow-up. RESULTS The cohort of genotype-positive LQTS patients included 212 patients, and 103 patients (49%, female n = 53, average follow-up 7.1 ± 4.0 years, average QTc 468 ± 42 ms) participated in sports. A total of 105 LQTS disease-causing mutations were identified: KCNQ1 n = 60 (58%), KCNH2 n = 36 (35%), SCN5A n = 6 (6%), KCNE1 n = 1 (1%), and KCNE2 n = 2 (2%). All patients were treated with beta-blockade, with noncompliance in 1 patient and intolerance in 1 patient. Twenty-six patients participated in competitive sports (26%, female n = 15, average follow-up 6.9 ± 4.1 years, average QTc 461 ± 35 ms). Seventy-seven patients (75%, female n = 35, average follow-up 7.3 ± 3.9 years, average QTc 470 ± 43 ms) participated in recreational sports. No patients had LQTS symptoms during sports participation. Five appropriate implantable cardioverter-defibrillator shocks occurred in 2 patients, though none were related to sports participation. CONCLUSIONS In this series no cardiac events and no deaths were observed in treatment-compliant LQTS children while participating in sports in 755 patient-years of follow-up. PMID:26301263

Chloroquine cardiotoxicity mimicking connective tissue disease heart involvement.

PubMed

Vereckei, András; Fazakas, Adám; Baló, Timea; Fekete, Béla; Molnár, Mária Judit; Karádi, István

2013-04-01

The authors report a case of rare chloroquine cardiotoxicity mimicking connective tissue disease heart involvement in a 56-year-old woman with mixed connective tissue disease (MCTD) manifested suddenly as third degree A-V block with QT(c) interval prolongation and short torsade de pointes runs ultimately degenerating into ventricular fibrillation. Immunological tests suggested an MCTD flare, implying that cardiac arrest had resulted from myocardial involvement by MCTD. However, QT(c) prolongation is not a characteristic of cardiomyopathy caused by connective tissue disease, unless anti-Ro/SSA positivity is present, but that was not the case. Therefore, looking for another cause of QT(c) prolongation the possibility of chloroquine cardiotoxicity emerged, which the patient had been receiving for almost two years in supramaximal doses. Biopsy of the deltoid muscle was performed, because in chloroquine toxicity, specific lesions are present both in the skeletal muscle and in the myocardium, and electron microscopy revealed the accumulation of cytoplasmic curvilinear bodies, which are specific to antimalarial-induced myocyte damage and are absent in all other muscle diseases, except neuronal ceroid lipofuscinosis. Thus, the diagnosis of chloroquine cardiotoxicity was established. It might be advisable to supplement the periodic ophthalmological examination, which is currently the only recommendation for patients on long-term chloroquine therapy, with ECG screening.

A comparative study of QT prolongation with serotonin reuptake inhibitors.

PubMed

Ojero-Senard, Ana; Benevent, Justine; Bondon-Guitton, Emmanuelle; Durrieu, Geneviève; Chebane, Leila; Araujo, Melanie; Montastruc, Francois; Montastruc, Jean-Louis

2017-10-01

QT interval prolongations were described with citalopram and escitalopram. However, the effects of the other serotonin reuptake inhibitors (SRIs) remained discussed. In order to identify a putative signal with other SRIs, the present study investigates the reports of QT interval prolongation with SRIs in two pharmacovigilance databases (PVDB). Two kinds of investigations were performed: (1) a comparative study in VigiBase®, the WHO PVDB, where notifications of QT prolongation with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were selected. Cases with overdose or pregnancy were excluded. The relationship between the "suspected" SRI and occurrence of QT prolongation was assessed by calculating reporting odds ratio (ROR) in a case/non-case design. (2) A descriptive study of QT prolongation reports with citalopram and escitalopram in the French FPVD. In VigiBase®, 855 notifications were identified (mean age 56.2 years, mainly women 73%). Among them, 172 (20.1%) were associated to escitalopram; 299 (35.0%), to citalopram; 186 (21.8%), to fluoxetine; 94 (11.0%), to sertraline; 66 (7.7%), to paroxetine; and 38 (4.4%) to fluvoxamine. A significant ROR value (higher than 1) was only found for citalopram (3.35 CI95% [2.90-3.87]) or escitalopram (2.50 [2.11-2.95]). In the FPVD, eight reports of QT prolongation were found with citalopram and 27 with escitalopram, mainly in women (77.1%) with a mean age of 73.2 years. In 23 cases (66%), SRIs were associated with other suspected drugs, mainly cardiotropic or psychotropic ones. Hypokalemia was associated in six patients. This study, performed in real conditions of life, shows a clear signal of QT prolongation with only two SRIs, citalopram and escitalopram, indicating that QT prolongation is not a SRI class effect.

Electrocardiographic findings in chronic hemodialysis patients.

PubMed

Bignotto, Luís Henrique; Kallás, Marina Esteves; Djouki, Rafael Jorge Teixeira; Sassaki, Marcela Mayume; Voss, Guilherme Ota; Soto, Cristina Lopez; Frattini, Fernando; Medeiros, Flávia Silva Reis

2012-01-01

Cardiovascular disease is the leading cause of mortality among patients on dialysis. When considering all causes of death, about 30% are classified as cardiac arrest, death of unknown cause or cardiac arrhythmia. The increasing time of ventricular depolarization and repolarization, measured non-invasively by measuring the QT interval on the electrocardiogram at rest, has emerged as a predictor of complex ventricular arrhythmias, a major cause of sudden cardiac death. To determine the electrocardiographic alterations present in hemodialysis (HD) patients, measuring the QT interval and its relationship with clinical and laboratory variables. Patients above 18 years on dialysis were approached to participate in the study and, after consent, were submitted to the examination of 12-lead electrocardiogram. Clinical data were reviewed to assess the presence of comorbidities, as well as anthropometric and blood pressure measures. Blood samples were collected to determinate hemoglobin and serum levels of calcium, phosphorus and potassium. One hundred and seventy nine patients were included in the study. The majority of the patients were male (64.8%) and white (54.7%); the average age was 58.5 ± 14.7 years old. About 50% of all patients had, at least, one electrical conduction disturb. About 50% of all patients had QTc prolongation and experienced a significant increase in the frequency of Left Ventricular Hypertrophy (LVH), changes of the cardiac rhythm and bundle branch blocks, and a lower body mass index (BMI), when compared with normal QTc interval patients. Patients with chronic kidney disease (CKD) on hemodialysis had high frequency of abnormal electrocardiographic findings, including a high prevalence of patients with prolonged QTc interval. This study also found a significant association between prolonged QTc interval and the presence of Diabetes and lower values of BMI.

Cardiovascular drugs inducing QT prolongation: facts and evidence.

PubMed

Taira, Carlos A; Opezzo, Javier A W; Mayer, Marcos A; Höcht, Christian

2010-01-01

Acquired QT syndrome is mainly caused by the administration of drugs that prolong ventricular repolarization. On the other hand, the risk of drug-induced torsades de pointes is increased by numerous predisposing factors, such as genetic predisposition, female sex, hypokalemia and cardiac dysfunction. This adverse reaction is induced by different chemical compounds used for the treatment of a variety of pathologies, including arrhythmias. As it is known, antiarrhythmic agents and other cardiovascular drugs can prolong the QT interval, causing this adverse reaction. Of the 20 most commonly reported drugs, 10 were cardiovascular agents and these appeared in 348 of the reports (46%). Class Ia antiarrhythmic agents have frequently been linked to inducing arrhythmia, including torsades de pointes. Sotalol and amiodarone, class III antiarrhythmics, are known to prolong the QT interval by blocking I(Kr). Due to the severity of events caused by the therapeutic use of these drugs, in this work of revision the cardiovascular drugs that present this property and the factors and evidence will be mentioned.

Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of IKs, but preserved cAMP-dependent up-regulation.

PubMed

Spätjens, Roel L H M G; Bébarová, Markéta; Seyen, Sandrine R M; Lentink, Viola; Jongbloed, Roselie J; Arens, Yvonne H J M; Heijman, Jordi; Volders, Paul G A

2014-10-01

Mutations in KCNQ1, encoding for Kv7.1, the α-subunit of the IKs channel, cause long-QT syndrome type 1, potentially predisposing patients to ventricular tachyarrhythmias and sudden cardiac death, in particular, during elevated sympathetic tone. Here, we aim at characterizing the p.Lys557Glu (K557E) Kv7.1 mutation, identified in a Dutch kindred, at baseline and during (mimicked) increased adrenergic tone. K557E carriers had moderate QTc prolongation that augmented significantly during exercise. IKs characteristics were determined after co-expressing Kv7.1-wild-type (WT) and/or K557E with minK and Yotiao in Chinese hamster ovary cells. K557E caused IKs loss of function with slowing of the activation kinetics, acceleration of deactivation kinetics, and a rightward shift of voltage-dependent activation. Together, these contributed to a dominant-negative reduction in IKs density. Confocal microscopy and western blot indicated that trafficking of K557E channels was not impaired. Stimulation of WT IKs by 3'-5'-cyclic adenosine monophosphate (cAMP) generated strong current up-regulation that was preserved for K557E in both hetero- and homozygosis. Accumulation of IKs at fast rates occurred both in WT and in K557E, but was blunted in the latter. In a computational model, K557E showed a loss of action potential shortening during β-adrenergic stimulation, in accordance with the lack of QT shortening during exercise in patients. K557E causes IKs loss of function with reduced fast rate-dependent current accumulation. cAMP-dependent stimulation of mutant IKs is preserved, but incapable of fully compensating for the baseline current reduction, explaining the long QT intervals at baseline and the abnormal QT accommodation during exercise in affected patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

Not all Beta-Blockers are Equal in the Management of Long QT Syndrome Types 1 and 2: Higher Recurrence of Events under Metoprolol

PubMed Central

Chockalingam, Priya; Crotti, Lia; Girardengo, Giulia; Johnson, Jonathan N.; Harris, Katy M.; van der Heijden, Jeroen F.; Hauer, Richard N.W.; Beckmann, Britt M.; Spazzolini, Carla; Rordorf, Roberto; Rydberg, Annika; Clur, Sally-Ann B.; Fischer, Markus; van den Heuvel, Freek; Kääb, Stefan; Blom, Nico A.; Ackerman, Michael J.; Schwartz, Peter J.; Wilde, Arthur A.M.

2012-01-01

Objectives To compare the efficacy of beta-blockers (BB) in congenital long QT syndrome (LQTS). Background BB are the mainstay in managing LQTS. Studies comparing the efficacy of commonly-used BB are lacking and clinicians generally assume they are equally effective. Methods ECG and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n=134), metoprolol (n=147), and nadolol (n=101) were analyzed, excluding patients aged <1 year at BB initiation. Symptoms prior to therapy and the first breakthrough cardiac events (BCEs) were documented. Results Patients (56% females, 27% symptomatic, HR 76±16 bpm, QTc 472±46 ms) were started on BB therapy at a median age of 14 years (IQR 8–32 years). QTc-shortening with propranolol was significantly greater than with other BB in the total cohort and in the subset with QTc >480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n=101), 15 had BCEs (all syncopes). QTc-shortening was significantly less-pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of other two BB combined, after adjustment for genotype (OR 3.95, 95% CI 1.2–13.1, p=0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients on metoprolol compared to propranolol/nadolol. Conclusions Propranolol has a significantly better QTc-shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used in symptomatic LQT1 and LQT2 patients. PMID:23083782

Changes in ST, QT and RR ECG intervals during acute stress in firefighters: a pilot study.

PubMed

Paiva, Joana S; Rodrigues, Susana; Cunha, Joao Paulo Silva

2016-08-01

Firefighting is a stressful occupation. The monitoring of psychophysiological measures in those professionals can be a way to prevent and early detect cardiac diseases and other stress-related problems. The current study aimed to assess morphological changes in the ECG signal induced by acute stress. A laboratory protocol was conducted among 6 firefighters, including a laboratory stress-inducer task - the Trier Social Stress Task (TSST) - and a 2-choice reaction time task (CRTT) that was performed before (CRTT1) and after (CRTT2) the stress condition. ECG signals were continuously acquired using the VitalJacket®, a wearable t-shirt that acts as a medical certified ECG monitor. Results showed that ECG morphological features such as QT and ST intervals are able to differentiate stressful from non stressful events in first responders. Group mean Visual Analogue Scale (VAS) for stress assessment significantly increased after the stress task (TSST), relatively to the end of CRTT2 (after TSST: 4.67±1.63; after CRTT2: 3.17±0.75), a change that was accompanied by a significant increase in group mean QT and ST segments corrected for heart rate during TSST. These encouraging results will be followed by larger studies in order to explore those measures and its physiological impact under realistic environments in a higher scalability.

Mental stress test: a rapid, simple, and efficient test to unmask long QT syndrome.

PubMed

Etienne, Pauline; Huchet, François; Gaborit, Nathalie; Barc, Julien; Thollet, Aurélie; Kyndt, Florence; Guyomarch, Béatrice; Le Marec, Hervé; Charpentier, Flavien; Schott, Jean-Jacques; Redon, Richard; Probst, Vincent; Gourraud, Jean-Baptiste

2018-04-20

QT prolongation during mental stress test (MST) has been associated with familial idiopathic ventricular fibrillation. In long QT syndrome (LQTS), up to 30% of mutation carriers have normal QT duration. Our aim was to assess the QT response during MST, and its accuracy in the diagnosis of concealed LQTS. All patients who are carrier of a KCNQ1 or KCNH2 mutations without QT prolongation were enrolled. A control group was constituted of patients with negative exercise and epinephrine tests. Electrocardiogram were recorded at rest and at the maximum heart rate during MST and reviewed by two physicians. Among the 70 patients enrolled (median age 41±2.1 years, 46% male), 36 were mutation carrier for LQTS (20 KCNQ1 and 16 KCNH2), and 34 were controls. KCNQ1 and KCNH2 mutation carriers presented a longer QT interval at baseline [405(389; 416) and 421 (394; 434) ms, respectively] compared with the controls [361(338; 375)ms; P < 0.0001]. QT duration during MST varied by 9 (4; 18) ms in KCNQ1, 3 (-6; 16) ms in KCNH2, and by -22 (-29; -17) ms in controls (P < 0.0001). These QT variations were independent of heart rate (P < 0.3751). Receiver operating characteristic curve analysis identified a cut-off value of QT variation superior to -11 ms as best predictor of LQTS. It provided 97% sensitivity and 97% specificity of QT prolongation in the diagnosis of LQTS. We identified a paradoxical response of the QT interval during MST in LQTS. Easy to assess, MST may be efficient to unmask concealed LQTS in patients at risk of this pathology.

Perioperative management of patients with congenital or acquired disorders of the QT interval.

PubMed

O'Hare, M; Maldonado, Y; Munro, J; Ackerman, M J; Ramakrishna, H; Sorajja, D

2018-04-01

QT prolongation can be attributable to various causes that can be categorised as acquired or congenital. Arrhythmias related to QT prolongation can result in clinical presentations, such as syncope and sudden cardiac death. The perioperative period presents a number of issues that may affect a patient's risk of developing polymorphic ventricular tachycardia or torsades de pointes. Although most patients may have an unremarkable perioperative course, some may have complications; this review article aims to help clinicians avoid potential complications, and to help them address treatment for perioperative issues that may occur. Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.

Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development

PubMed Central

Salvi, Vaibhav; Karnad, Dilip R; Panicker, Gopi Krishna; Kothari, Snehal

2010-01-01

Following reports of death from cardiac arrhythmias with drugs like terfenadine and cisapride, the International Conference for Harmonization formulated a guidance (E14) document. This specifies that all new drugs must undergo a ‘thorough QT/QTc’ (TQT) study to detect drug-induced QT prolongation, a surrogate marker of ventricular tachycardia, especially torsades de pointes (TdPs). With better understanding of data from several completed TQT studies, regulatory requirements have undergone some changes since the E14 guidance was implemented in October 2005. This article reviews the implications of the E14 guidance and the changes in its interpretation including choice of baseline QT, demonstration of assay sensitivity, statistical analysis of the effect of new drug and positive control, and PK-PD modelling. Some issues like use of automated QT measurements remain unresolved. Pharmaceutical companies too are modifying Phase 1 studies to detect QTc liability early in order to save time and resources. After the E14 guidance, development of several drugs that prolong QTc by >5 ms is being abandoned by sponsors. However, all drugs that prolong the QT interval do not increase risk of TdP. Researchers in regulatory agencies, academia and industry are working to find better biomarkers of drug-induced TdP which could prevent many useful drugs from being prematurely abandoned. Drug-induced TdP is a rare occurrence. With fewer drugs that prolong QT interval reaching the licensing stage, knowing which of these drugs are torsadogenic is proving to be elusive. Thus, paradoxically, the effectiveness of the E14 guidance itself has made prospective validation of new biomarkers difficult. This article is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010 PMID:19775279

The Association between Work-Related Stress and Autonomic Imbalance among Call Center Employees in Japan.

PubMed

Enoki, Mamiko; Maeda, Eri; Iwata, Toyoto; Murata, Katsuyuki

2017-12-01

There is little epidemiological evidence linking subjective stress to objective etiologic indicators. To clarify an association between work-related stress and autonomic nervous function, we examined call center employees (167 males and 371 females) undergoing electrocardiography (ECG) at the time of annual health checkups. The questionnaire was composed of the Brief Job Stress Questionnaire based on the demand-control-support model and the Social Readjustment Rating Scale including detailed contents of home stress. The Bazett's corrected QT (QTc) interval, QT index, and heart rate were obtained from the ECG data. The male employees showed significantly higher scores of job demand, job control, and supervisor support than the female ones. In the male employees, QT index indicating the extent of autonomic imbalance and heart rate were associated with high score of supervisor support and low score of coworker support (P < 0.05), but no significant relationships were seen between QTc interval and either job strain (i.e., job demand and job control) or home stress. By contrast, the female employees showed no significant links between any autonomic indicators and either work-related stress or home stress. These data suggest that work-related stress affected QT index in male employees suffering specific occupational stressors such as emotional abuse from unsatisfied customers. Specifically, supports from supervisors and coworkers were paradoxically associated with QT index, implying that supervisors may have failed to effectively support such male employees. Also, autonomic nervous function in male employees appears to be more vulnerable to work-related stress than that in female ones.

Concentration-Response Modeling of ECG Data From Early-Phase Clinical Studies as an Alternative Clinical and Regulatory Approach to Assessing QT Risk - Experience From the Development Program of Lemborexant.

PubMed

Murphy, Patricia J; Yasuda, Sanae; Nakai, Kenya; Yoshinaga, Takashi; Hall, Nancy; Zhou, Meijian; Aluri, Jagadeesh; Rege, Bhaskar; Moline, Margaret; Ferry, Jim; Darpo, Borje

2017-01-01

Lemborexant is a novel dual orexin receptor antagonist being developed to treat insomnia. Its potential to cause QT prolongation was evaluated using plasma concentration-response (CR) modeling applied to data from 2 multiple ascending-dose (MAD) studies. In the primary MAD study, placebo or lemborexant (2.5 to 75 mg) was administered for 14 consecutive nights. In another MAD study designed to "bridge" pharmacokinetic and safety data between Japanese and non-Japanese subjects (J-MAD), placebo or lemborexant (2.5, 10, or 25 mg) was administered for 14 consecutive nights. QT intervals were estimated using a high-precision measurement technique and evaluated using a linear mixed-effects CR model, for each study separately and for the pooled data set. When each study was analyzed separately, the slopes of the CR relationship were shallow and not statistically significant. In the pooled analysis, the slope of the CR relationship was -0.00002 milliseconds per ng/mL (90%CI, -0.01019 to 0.01014 milliseconds). The highest observed C max was 400 ng/mL, representing a margin 8-fold above exposures expected for the highest planned clinical dose. The model-predicted QTc effect at 400 ng/mL was 1.1 milliseconds (90%CI, -3.49 to 5.78 milliseconds). In neither the J-MAD study nor the pooled analysis was an effect of race identified. CR modeling of data from early-phase clinical studies, including plasma levels far exceeding those anticipated clinically, indicated that a QT effect >10 milliseconds could be excluded. Regulatory agreement with this methodology demonstrates the effectiveness of a CR modeling approach as an alternative to thorough QT studies. © 2016, The American College of Clinical Pharmacology.

Tp-Te interval predicts heart rate reduction after fingolimod administration in patients with multiple sclerosis.

PubMed

Tocci, Giuliano; Giuliani, Manuela; Canichella, Flaminia; Timpano, Jacopo; Presta, Vivianne; Francia, Pietro; Musumeci, Maria Beatrice; Fubelli, Federica; Pozzilli, Carlo; Volpe, Massimo; Ferrucci, Andrea

2016-10-15

FTY720 (Fingolimod) is an immunosuppressive drug, which provides favourable effects in patients with multiple sclerosis (MS), albeit it induces heart rate (HR) and blood pressure (BP) reductions. Therefore, we tested potential factors able to predict HR response in MS patients treated with fingolimod. We analysed patients with MS followed at our Neurology Outpatient Clinic from May 2013 to June 2015. All patients underwent BP measurements and 12-lead ECG before and 6-h after drug administration. At these time intervals, conventional and new ECG indexes for cardiac damage, including Tp-Te interval, were measured. Univariate and multivariate analyses were performed to test the outcome of HR reduction more than median difference between baseline and final observations. 69 outpatients with MS (46 males, age 35.1±9.4years, BP 119.0±12.7/73.0±9.3mmHg, HR 73.5±11.4bpm) were included. No relevant adverse reactions were reported. Fingolimod induced progressive systolic (P=0.024) and diastolic (P<0.001) BP, as well as HR (P<0.001) reductions compared to baseline. Prolonged PQ (150.4±19.5 vs. 157.0±19.5ms; P<0.001), QT (374.9±27.0 vs. 400.0±25.8ms; P<0.001), Tp-Te (1.8±0.3 vs. 1.9±0.3mm; P=0.021), and reduced QTc (414.4±24.4 vs. 404.5±24.5ms; P<0.001) intervals were also recorded at final observation. Baseline HR, QT and Tp-Te intervals provided prognostic information at univariate analysis, although Tp-Te interval resulted the best independent predictor for HR reduction at multivariate analysis [0.057 (0.005-0.660); P=0.022]. This study firstly demonstrates that prolonged Tp-Te interval may identify those MS patients treated with fingolimod at higher risk of having significant, asymptomatic HR reduction during clinical observation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The QT interval in lightning injury with implications for the cessation of metabolism hypothesis

NASA Technical Reports Server (NTRS)

Andrews, Christopher J.; Colquhoun, David M.; Darveniza, Mat

1991-01-01

An hypothesis is presented to provide an alternative to the Cessation of Metabolism hypothesis often invoked in lightning injury. Cessation of Metabolism has been proposed to explain the observation of good recovery after a prolonged period in cardiac arrest in some lightning injured patients. Reevaluation of EEGs from lightning injured patients show a high incidence of QT prolongation. Reexamination of the cases used to support Cessation of Metabolism also reveals little evidence to justify the hypothesis. The finding of QT prolongation coupled with the hyperadrenergic state said to exist in lightning injury, may promote a state of episodic induction of and recovery from Torsade de Pointes Ventricular Tachycardia (VT). Histological examination of the myocardium supports the new hypothesis. This the first concerted description of lightning injury as one of the general causes of QT prolongation. It appears to occur frequently after lightning injury, is a prerequisite of and predisposes to episodes of Torsade de Pointes VT. These electrocardiographic abnormalities explain Cessation of Metabolism and recognition may change management and lead to greater survival.

Electrocardiographic and blood pressure effects of energy drinks and Panax ginseng in healthy volunteers: A randomized clinical trial.

PubMed

Shah, Sachin A; Occiano, Andrew; Nguyen, Tinh An; Chan, Amanda; Sky, Joseph C; Bhattacharyya, Mouchumi; O'Dell, Kate M; Shek, Allen; Nguyen, Nancy N

2016-09-01

Energy drink usage has been linked to emergency room visits and deaths. The objective of the study is to assess the electrocardiographic and blood pressure effects of energy drinks, Panax ginseng and placebo in healthy individuals. This was a randomized, double blinded, placebo controlled, crossover study. Young healthy volunteers with no comorbid conditions consumed 32oz of an energy drink, control drink with 800mg of Panax ginseng or matching placebo-control drink over 45min. Primary endpoints were QTc interval and systolic blood pressure. Secondary endpoints included QT interval, PR interval, QRS duration, heart rate, and diastolic blood pressure. All endpoints were assessed at baseline, 1, 2, 3.5, and 5.5h. A significant increase in QTc interval 2h post energy drink consumption was evident when compared to placebo (3.37±10.7ms and -3.19±11.8ms respectively; p=0.030). Similarly, systolic blood pressure 2h post energy drink consumption increased when compared to placebo (2.00±6.37mmHg and -2.67±5.83mmHg respectively; p=0.014). The PR interval significantly reduced over a 2h period post energy drink use in a clinically non-meaningful manner. Heart rate at 2h was not significantly higher in the energy drink group when compared to others. The QT interval, QRS interval and diastolic blood pressure were not impacted at any time point. Certain energy drinks consumed at a high volume significantly increase the QTc interval and systolic blood pressure by over 6ms and 4mmHg respectively. Panax ginseng does not have a significant impact on ECG or blood pressure parameters. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Sleep-disordered breathing is associated with disturbed cardiac repolarization in patients with a coronary artery bypass graft surgery.

PubMed

Schmidleitner, Christina; Arzt, Michael; Tafelmeier, Maria; Ripfel, Sarah; Fauser, Miriam; Weizenegger, Teresa; Flörchinger, Bernhard; Camboni, Daniele; Wittmann, Sigrid; Zeman, Florian; Schmid, Christof; Maier, Lars S; Wagner, Stefan; Fisser, Christoph

2018-02-01

The development of malignant ventricular arrhythmias due to abnormal cardiac repolarization is a major complication after coronary artery bypass graft surgery (CABG). Sleep-disordered breathing (SDB) is linked to prolonged cardiac repolarization in non-surgical patients. This study evaluates cardiac repolarization in patients with and without SDB who underwent CABG. 100 patients who had received CABG (84% men, age 68 ± 10 years, body-mass-index [BMI] 28.7 ± 4.2 kg/m 2 ) were retrospectively evaluated. Polygraphy was recorded the night before CABG. SDB was defined as an apnea-hypopnea index (AHI) of ≥15/h and differentiated into central (CSA) and obstructive (OSA) sleep apnea. Cardiac repolarization was assessed by means of T-peak-to-end (TpTe) and QTc-intervals and TpTe/QT-ratios derived from 12-lead electrocardiography (ECG). 37% of patients had SDB, 14% CSA and 23% OSA. Before CABG, patients with CSA and OSA had longer TpTe intervals than those without SDB (TpTe: CSA 100 ± 26 vs. OSA 97 ± 19 vs. no SDB 85 ± 14 ms, p = 0.013). QTc intervals and TpTe/QT ratios differed between the two groups (QTc: 444 ± 54 vs. 462 ± 36 vs. 421 ± 32 ms, p < 0.001; TpTe/QT ratio: 0.24 ± 0.04 vs. 0.23 ± 0.05 vs. 0.21 ± 0.03, p = 0.045). SDB was associated with abnormal cardiac repolarization independent of known risk factors for cardiac arrhythmias, such as age, sex, BMI, N-terminal-pro-brain-natriuretic-peptide (NT-proBNP), and heart failure (TpTe: B-coefficient [95%CI]: 16.0, [7.6-24.3], p < 0.001; QTc: 27.2 [9.3-45.1], p = 0.003; TpTe/QT ratio: 2.9 [1.2-4.6], p < 0.001). Independent of known risk factors for cardiac arrhythmias, SDB was significantly associated with abnormal cardiac repolarization before CABG. Data suggest that SDB may contribute to an increased risk of ventricular arrhythmias after CABG. Copyright © 2018 Elsevier B.V. All rights reserved.

The Effects of Local Anaesthetics on QT Parameters during Thoracic Epidural Anaesthesia Combined with General Anaesthesia: Ropivacaine versus Bupivacaine

PubMed Central

Güven, Özlem; Sazak, Hilal; Alagöz, Ali; Şavkılıoğlu, Eser; Demirbaş, Çilsem Sevgen; Yıldız, Ali; Karabulut, Erdem

2013-01-01

Background: Many studies focusing on the effects of local anaesthetics on QT intervals have been performed, but the articles evaluating the relationship between thoracic epidural anaesthesia combined with general anaesthesia and QT parameters are very limited. Aims: We aimed to compare the effects of bupivacaine and ropivacaine on QT interval, corrected QT, dispersion of QT, and corrected dispersion of QT in patients undergoing lung resection under thoracic epidural anaesthesia combined with general anaesthesia. Study Design: Prospective clinical study. Methods: Thirty ASA physical status 1–3 patients requiring thoracic epidural anaesthesia combined with general anaesthesia for thoracic surgery. Patients were randomly assigned to two groups, which were allocated to receive either bupivacaine (Group B) or ropivacaine (Group R) during thoracic epidural anaesthesia. Following haemodynamic monitoring, a thoracic epidural catheter was inserted. Local anaesthetic at an average dose of 1.5 mL/ segment was given through an epidural catheter. The same general anaesthesia protocol was administered in both groups. Records and measurements were performed on 10 phases that were between the thoracic epidural catheter insertion to the 5th min of endobronchial intubation. In all phases, systolic arterial pressure, diastolic arterial pressure, mean arterial pressure, heart rate, peripheral O2 saturation, and electrocardiogram monitoring were performed in patients. All QT parameters were recorded by 12-lead electrocardiogram and analysed manually by a cardiologist. Results: QT intervals were similar between two groups. In Group R, corrected QT values at the 20th min of local anaesthetic injection and the 5th min of endobronchial intubation were shorter than those in Group B (p<0.05). The basal dispersion of QT and dispersion of QT values at the 1st min of propofol injection were shorter than those in Group R (p<0.05). The corrected dispersion of QT value at the 1st min of propofol

Short-term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high-frequency autonomic oscillations

PubMed Central

Champeroux, P; Thireau, J; Judé, S; Laigot-Barbé, C; Maurin, A; Sola, M L; Fowler, J S L; Richard, S; Le Guennec, J Y

2015-01-01

Background and Purpose The present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated K+ channel, hERG, on cardiac autonomic control. Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency. Experimental Approach The short-term variability of beat-to-beat QT interval (STVQT), induced by dofetilide is a strong surrogate of Torsades de pointes liability. Involvement of autonomic modulation in STVQT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium. Key Results Increase in STVQT induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and QT interval high-frequency (HF) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when HF oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate HF oscillations were found in dogs with other hERG blockers described as causing Torsades de pointes in humans. Conclusions and Implications These results demonstrate for the first time that beat-to-beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous HF autonomic oscillations in heart rate. When combined with evidence of hERG-blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STVQT for Torsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals. PMID:25625756

Short-term variability in QT interval and ventricular arrhythmias induced by dofetilide are dependent on high-frequency autonomic oscillations.

PubMed

Champeroux, P; Thireau, J; Judé, S; Laigot-Barbé, C; Maurin, A; Sola, M L; Fowler, J S L; Richard, S; Le Guennec, J Y

2015-06-01

The present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated K(+) channel, hERG, on cardiac autonomic control. Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency. The short-term variability of beat-to-beat QT interval (STVQT ), induced by dofetilide is a strong surrogate of Torsades de pointes liability. Involvement of autonomic modulation in STVQT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium. Increase in STVQT induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and QT interval high-frequency (HF) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when HF oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate HF oscillations were found in dogs with other hERG blockers described as causing Torsades de pointes in humans. These results demonstrate for the first time that beat-to-beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous HF autonomic oscillations in heart rate. When combined with evidence of hERG-blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STVQT for Torsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals. © 2015 The British Pharmacological Society.

Tpeak - Tend and Tpeak - Tend /QT ratio as markers of ventricular arrhythmia risk in cardiac resynchronization therapy patients.

PubMed

Barbhaiya, Chirag; Po, Jose Ricardo F; Hanon, Sam; Schweitzer, Paul

2013-01-01

Cardiac resynchronization therapy (CRT) increases transmural dispersion of repolarization (TDR) and can be pro-arrhythmic. However, overall arrhythmia risk was not increased in large-scale CRT clinical trials. Increased TDR as measured by T(peak ) -T(end) (TpTe) was associated with arrhythmia risk in CRT in a single-center study. This study investigates whether QT interval, TpTe, and TpTe/QT ratio are associated with ventricular arrhythmias in patients with CRT-defibrillator (CRT-D). Post-CRT-D implant electrocardiograms of 128 patients (age 71.3 years ± 10.3) with at least 2 months of follow-up at our institution's device clinic (mean follow-up of 28.5 months ± 17) were analyzed for QT interval, TpTe, and TpTe/QT ratio. Incidence of ventricular arrhythmias was determined based on routine and directed device interrogations. Appropriate implantable cardioverter-defibrillator therapy for sustained ventricular tachycardia or ventricular fibrillation was delivered in 18 patients (14%), and nonsustained ventricular tachycardia (NSVT) was detected but did not require therapy in 58 patients (45%). Patients who received appropriate defibrillator therapy had increased TpTe/QT ratio (0.24 ± 0.03 ms vs 0.20 ± 0.04, P = 0.0002) and increased TpTe (105.56 ± 20.36 vs 87.82 ± 22.32 ms, P = 0.002), and patients with NSVT had increased TpTe/QT ratio (0.22 ± 0.04 vs 0.20 ± 0.04, P = 0.016). Increased QT interval was not associated with risk of ventricular arrhythmia. The relative risk for appropriate defibrillator therapy of T(p) T(e) /QT ratio ≥ 0.25 was 3.24 (P = 0.016). Increased TpTe and increased TpTe/QT ratio are associated with increased incidence of ventricular arrhythmias in CRT-D. The utility of TpTe interval and TpTe/QT ratio as potentially modifiable risk factors for ventricular arrhythmias in CRT requires further study. ©2012, The Authors. Journal compilation ©2012 Wiley Periodicals, Inc.

Aging modulates dispersion of ventricular repolarization in the very old of the geriatric population.

PubMed

Huang, Jen-Hung; Lin, Ying-Qin; Pan, Nan-Hung; Chen, Yi-Jen

2010-11-01

Aging plays an essential role in cardiac pathophysiology. Knowledge on the ventricular repolarization in very old individuals is limited. An increase of QT dispersion is associated with higher cardiovascular mortality. The purpose of this study is to investigate whether aging changes the QT dispersion in the very old. Heart rate, P wave duration, PR interval, QRS axis, QRS duration, QT interval, and QTc interval were measured from 12-lead resting ECG. QT dispersion (46 ± 21, 47 ± 17, 69 ± 31 ms, p < 0.005) was significantly increased in the age group ≧85 years (n = 29, 89 ± 4 years) than in the age group 75-84 years (n = 33, 79 ± 3 years) and the age group 65-74 years (n = 32, 68 ± 3 years). Aging modulates dispersion of ventricular repolarization, which may contribute to the cardiac mortality in the very old Asian population.

Contribution of a KCNH2 variant in genotyped long QT syndrome: Romano-Ward syndrome under double mutations and acquired long QT syndrome under heterozygote.

PubMed

Fujii, Yusuke; Matsumoto, Yuichi; Hayashi, Kenshi; Ding, Wei-Guang; Tomita, Yukinori; Fukumoto, Daisuke; Wada, Yuko; Ichikawa, Mari; Sonoda, Keiko; Ozawa, Junichi; Makiyama, Takeru; Ohno, Seiko; Yamagishi, Masakazu; Matsuura, Hiroshi; Horie, Minoru; Itoh, Hideki

2017-07-01

Long QT syndrome (LQTS) presents two clinical phenotypes, congenital and acquired forms. This study aims to evaluate the genetic contribution of a KCNH2 variant for the two LQTS phenotypes. From 1996 to 2014, genetic screening for LQTS probands was performed for five major genes: KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 and 389 probands were found to be mutation carriers. We analyzed the clinical phenotypes of p.His492Tyr carriers in KCNH2. Heterozygous p.His492Tyr variant was identified in 10 LQTS families. Six probands (mean age, 26±23 years) carried another mutation, and two of six had syncope associated with emotional stress or telephone ringing. The remaining four probands were significantly older at diagnosis (mean age, 42±33 years) and carried no other compound mutations. All the four probands had fatal arrhythmic events in the presence of additional precipitating factors such as culprit drugs in 2, hypokalemia in 1, and bradycardia in 1. The QTc interval of carriers with p.His492Tyr alone was 445±10ms and significantly shorter than that in double mutation carriers (481±40ms, p=0.041). KCNH2 p.His492Tyr variant presented Romano-Ward syndrome in the presence of another mutation and heterozygous carriers had mild phenotypes while even heterozygous carriers should be cared for not to encounter secondary factors because incidental factors could manifest "latent" form of p.His492Tyr heterozygous carriers. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Determinants of torsades de pointes in older patients with drug-associated long QT syndrome: a case-control study.

PubMed

Goutelle, Sylvain; Sidolle, Elodie; Ducher, Michel; Caron, Jacques; Timour, Quadiri; Nony, Patrice; Gouraud, Aurore

2014-08-01

Many elderly patients are routinely exposed to drugs that may prolong the cardiac QT interval and cause Torsades de pointes (TdP). However, predictors of TdP in patients with drug-associated long QT syndrome (LQTS) are not fully understood, especially in the geriatric population. The objective of this study was to identify risk factors of TdP in elderly patients with drug-associated LQTS. In this retrospective, case-control study, documented reports of drug-associated LQTS plus TdP (n = 125) and LQTS without TdP (n = 81) in patients ≥65 years of age were retrieved from the French Pharmacovigilance Database over a 10-year period. Available clinical, biological, and drug therapy data were compared in the two groups and logistic regression was performed to identify significant predictors of TdP. The uncorrected QT interval was significantly longer in patients with TdP than in patients without TdP (577 ± 79 vs. 519 ± 68 ms; p = 0.0001). The number of drugs with a known risk of TdP administered to each patient was not a predictor of arrhythmia, nor was female gender. Logistic regression analysis identified the uncorrected QT interval as the only significant predictor of TdP. The receiver operating characteristic curve analysis was characterized by an area under the curve of 0.77 (95 % confidence interval 0.64-0.88) and a QT cutoff of 550 ms. The uncorrected QT interval was significantly associated with the probability of TdP in elderly patients with acquired, drug-associated LQTS.

Prevalence and Spectrum of Large Deletions or Duplications in the Major Long QT Syndrome-Susceptibility Genes and Implications for Long QT Syndrome Genetic Testing

PubMed Central

Tester, David J.; Benton, Amber J.; Train, Laura; Deal, Barbara; Baudhuin, Linnea M.; Ackerman, Michael J.

2010-01-01

Long QT Syndrome (LQTS) is a cardiac channelopathy associated with syncope, seizures, and sudden death. Approximately 75% of LQTS is due to mutations in genes encoding for three cardiac ion channel alpha-subunits (LQT1-3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. Here, we set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS-susceptibility genes among unrelated patients who were mutation-negative following point mutation analysis of LQT1-12-susceptibility genes. Forty-two unrelated clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification (MLPA), a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA-MLPA LQTS Kit from MRC-Holland was used to analyze the three major LQTS-associated genes: KCNQ1, KCNH2, and SCN5A and the two minor genes: KCNE1 and KCNE2. Overall, 2 gene rearrangements were found in 2/42 (4.8%, CI, 1.7–11%) unrelated patients. A deletion of KCNQ1 exon 3 was identified in a 10 year-old Caucasian boy with a QTc of 660 milliseconds (ms), a personal history of exercise-induced syncope, and a family history of syncope. A deletion of KCNQ1 exon 7 was identified in a 17 year-old Caucasian girl with a QTc of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, since nearly 5% of patients with genetically elusive LQTS had large genomic rearrangements involving the canonical LQTS-susceptibility genes, reflex genetic testing to investigate genomic rearrangements may be of clinical value. PMID:20920651

QT and JT dispersion and cardiac performance in children with neonatal Bartter syndrome: a pilot study.

PubMed

Hacihamdioglu, Duygu Ovunc; Fidanci, Kursat; Kilic, Ayhan; Gok, Faysal; Topaloglu, Rezan

2013-10-01

QT dispersion and JT dispersion are simple noninvasive arrhythmogenic markers that can be used to assess the homogeneity of cardiac repolarization. The aim of this study was to assess QT and JT dispersion and their relation with left ventricular systolic and diastolic functions in children with Bartter syndrome (BS). Nine neonatal patients with BS (median age 9.7 years) and 20 controls (median age 8 years) were investigated at rest. Both study and control subjects underwent electrocardiography (ECG) in which the interval between two R waves and QT intervals, corrected QT, QT dispersion, corrected QT dispersion, JT, corrected JT, JT dispersion and corrected JT dispersion were measured with 12-lead ECG. Two-dimensional, Doppler echocardiographic examinations were performed. Patients and controls did not differ for gender and for serum levels of potassium, magnesium, and calcium (p > 0.05). Both study and control subjects had normal echocardiographic examination and baseline myocardial performance indexes. The QT dispersion and JT dispersion were significantly prolonged in patients with BS compared to those of the controls {37.5 ms [interquartile range (IQR) 32.5-40] vs. 25.5 ms (IQR 20-30), respectively, p = 0.014 and 37.5 ms (IQR 27.5-40) vs. 22.5 ms (IQR 20-30), respectively, p = 0.003}. Elevated QT and JT dispersion during asymptomatic and normokalemic periods may be risk factors for the development of cardiac complications and arrhythmias in children with BS. In these patients the need for systematic cardiac screening and management protocol is extremely important for effective prevention.

Adjustment of QT dispersion assessed from 12 lead electrocardiograms for different numbers of analysed electrocardiographic leads: comparison of stability of different methods.

PubMed Central

Hnatkova, K; Malik, M; Kautzner, J; Gang, Y; Camm, A J

1994-01-01

OBJECTIVE--Normal electrocardiographic recordings were analysed to establish the influence of measurement of different numbers of electrocardiographic leads on the results of different formulas expressing QT dispersion and the effects of adjustment of QT dispersion obtained from a subset of an electrocardiogram to approximate to the true QT dispersion obtained from a complete electrocardiogram. SUBJECTS AND METHODS--Resting 12 lead electrocardiograms of 27 healthy people were investigated. In each lead, the QT interval was measured with a digitising board and QT dispersion was evaluated by three formulas: (A) the difference between the longest and the shortest QT interval among all leads; (B) the difference between the second longest and the second shortest QT interval; (C) SD of QT intervals in different leads. For each formula, the "true" dispersion was assessed from all measurable leads and then different combinations of leads were omitted. The mean relative differences between the QT dispersion with a given number of omitted leads and the "true" QT dispersion (mean relative errors) and the coefficients of variance of the results of QT dispersion obtained when omitting combinations of leads were compared for the different formulas. The procedure was repeated with an adjustment of each formula dividing its results by the square root of the number of measured leads. The same approach was used for the measurement of QT dispersion from the chest leads including a fourth formula (D) the SD of interlead differences weighted according to the distances between leads. For different formulas, the mean relative errors caused by omitting individual electrocardiographic leads were also assessed and the importance of individual leads for correct measurement of QT dispersion was investigated. RESULTS--The study found important differences between different formulas for assessment of QT dispersion with respect to compensation for missing measurements of QT interval. The

Long-Term Haloperidol Treatment Prolongs QT Interval and Increases Expression of Sigma 1 and IP3 Receptors in Guinea Pig Hearts.

PubMed

Stracina, Tibor; Slaninova, Iva; Polanska, Hana; Axmanova, Martina; Olejnickova, Veronika; Konecny, Petr; Masarik, Michal; Krizanova, Olga; Novakova, Marie

2015-07-01

Haloperidol is a neuroleptic drug used for a medication of various psychoses and deliria. Its administration is frequently accompanied by cardiovascular side effects, expressed as QT interval prolongation and occurrence of even lethal arrhythmias. Despite these side effects, haloperidol is still prescribed in Europe in clinical practice. Haloperidol binds to sigma receptors that are coupled with inositol 1,4,5-trisphosphate (IP3) receptors. Sigma receptors are expressed in various tissues, including heart muscle, and they modulate potassium channels. Together with IP3 receptors, sigma receptors are also involved in calcium handling in various tissues. Therefore, the present work aimed to study the effects of long-term haloperidol administration on the cardiac function. Haloperidol (2 mg/kg once a day) or vehiculum was administered by intraperitoneal injection to guinea pigs for 21 consecutive days. We measured the responsiveness of the hearts isolated from the haloperidol-treated animals to additional application of haloperidol. Expression of the sigma 1 receptor and IP3 receptors was studied by real time-PCR and immunohistochemical analyses. Haloperidol treatment caused the significant decrease in the relative heart rate and the prolongation of QT interval of the isolated hearts from the haloperidol-treated animals, compared to the hearts isolated from control animals. The expression of sigma 1 and IP3 type 1 and type 2 receptors was increased in both atria of the haloperidol-treated animals but not in ventricles. The modulation of sigma 1 and IP3 receptors may lead to altered calcium handling in cardiomyocytes and thus contribute to changed sensitivity of cardiac cells to arrhythmias.

Comparison of automated measurements of electrocardiographic intervals and durations by computer-based algorithms of digital electrocardiographs.

PubMed

Kligfield, Paul; Badilini, Fabio; Rowlandson, Ian; Xue, Joel; Clark, Elaine; Devine, Brian; Macfarlane, Peter; de Bie, Johan; Mortara, David; Babaeizadeh, Saeed; Gregg, Richard; Helfenbein, Eric D; Green, Cynthia L

2014-02-01

Automated measurements of electrocardiographic (ECG) intervals are widely used by clinicians for individual patient diagnosis and by investigators in population studies. We examined whether clinically significant systematic differences exist in ECG intervals measured by current generation digital electrocardiographs from different manufacturers and whether differences, if present, are dependent on the degree of abnormality of the selected ECGs. Measurements of RR interval, PR interval, QRS duration, and QT interval were made blindly by 4 major manufacturers of digital electrocardiographs used in the United States from 600 XML files of ECG tracings stored in the US FDA ECG warehouse and released for the purpose of this study by the Cardiac Safety Research Consortium. Included were 3 groups based on expected QT interval and degree of repolarization abnormality, comprising 200 ECGs each from (1) placebo or baseline study period in normal subjects during thorough QT studies, (2) peak moxifloxacin effect in otherwise normal subjects during thorough QT studies, and (3) patients with genotyped variants of congenital long QT syndrome (LQTS). Differences of means between manufacturers were generally small in the normal and moxifloxacin subjects, but in the LQTS patients, differences of means ranged from 2.0 to 14.0 ms for QRS duration and from 0.8 to 18.1 ms for the QT interval. Mean absolute differences between algorithms were similar for QRS duration and QT intervals in the normal and in the moxifloxacin subjects (mean ≤6 ms) but were significantly larger in patients with LQTS. Small but statistically significant group differences in mean interval and duration measurements and means of individual absolute differences exist among automated algorithms of widely used, current generation digital electrocardiographs. Measurement differences, including QRS duration and the QT interval, are greatest for the most abnormal ECGs. © 2014.

Evaluation of the Relationship Between Pharmacokinetics and the Safety of Aripiprazole and Its Cardiovascular Effects in Healthy Volunteers.

PubMed

Belmonte, Carmen; Ochoa, Dolores; Román, Manuel; Cabaleiro, Teresa; Talegón, Maria; Sánchez-Rojas, Sergio Daniel; Abad-Santos, Francisco

2016-12-01

The aim of this study was the evaluation of the possible relationship between pharmacokinetics and the safety of aripiprazole as well as its influence on blood pressure (BP), heart rate (HR), and corrected QT (QTc) interval. The study population comprised 157 healthy volunteers from 6 bioequivalence clinical trials. Subjects were administered a single 10-mg oral dose of each formulation separated by a 28-day washout period. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. Blood pressure was measured at the following times: predose and 0.5, 2, 4, 6, and 8 hours postdose. An electrocardiogram was recorded at predose, 4, and 8 hours postdose. Area under the curve (AUC), maximum plasma concentration, half-life, and distribution volume corrected for weight were higher in women. Aripiprazole treatment produced a decrease of BP (9.3 mm Hg on systolic and 6.2 mm Hg on diastolic pressure) and an increase in HR (12.1 beats per minute) and QTc interval (9.1 milliseconds). There were sex differences in BP, HR, and QTc interval. Women and subjects with higher AUC and maximum plasma concentration values were more prone to experience adverse drug reactions and gastrointestinal adverse reactions. The AUC was related with systolic BP and diastolic BP decrease and HR increase but there was no relationship between aripiprazole concentrations and QTc increase. Aripiprazole decreases BP and increases HR and QTc interval. Pharmacokinetics, pharmacodynamics, and safety of aripiprazole are affected by sex. There is a directly proportional relationship between pharmacokinetic parameters and adverse drug reactions and effect on BP and HR.

Classification and Reporting of Potentially Proarrhythmic Common Genetic Variation in Long QT Syndrome Genetic Testing.

PubMed

Giudicessi, John R; Roden, Dan M; Wilde, Arthur A M; Ackerman, Michael J

2018-02-06

The acquired and congenital forms of long QT syndrome represent 2 distinct but clinically and genetically intertwined disorders of cardiac repolarization characterized by the shared final common pathway of QT interval prolongation and risk of potentially life-threatening arrhythmias. Over the past 2 decades, our understanding of the spectrum of genetic variation that (1) perturbs the function of cardiac ion channel macromolecular complexes and intracellular calcium-handling proteins, (2) underlies acquired/congenital long QT syndrome susceptibility, and (3) serves as a determinant of QT interval duration in the general population has grown exponentially. In turn, these molecular insights led to the development and increased utilization of clinically impactful genetic testing for congenital long QT syndrome. However, the widespread adoption and potential misinterpretation of the 2015 American College of Medical Genetics and Genomics variant classification and reporting guidelines may have contributed unintentionally to the reduced reporting of common genetic variants, with compelling epidemiological and functional evidence to support a potentially proarrhythmic role in patients with congenital and acquired long QT syndrome. As a result, some genetic testing reports may fail to convey the full extent of a patient's genetic susceptibility for a potentially life-threatening arrhythmia to the ordering healthcare professional. In this white paper, we examine the current classification and reporting (or lack thereof) of potentially proarrhythmic common genetic variants and investigate potential mechanisms to facilitate the reporting of these genetic variants without increasing the risk of diagnostic miscues. © 2018 American Heart Association, Inc.

Population pharmacokinetics and pharmacodynamics of escitalopram in overdose and the effect of activated charcoal

PubMed Central

van Gorp, Freek; Duffull, Stephen; Hackett, L Peter; Isbister, Geoffrey K

2012-01-01

AIMS To describe the pharmacokinetics and pharmacodynamics (PKPD) of escitalopram in overdose and its effect on QT prolongation, including the effectiveness of single dose activated charcoal (SDAC). METHODS The data set included 78 escitalopram overdose events (median dose, 140 mg [10–560 mg]). SDAC was administered 1.0 to 2.6 h after 12 overdoses (15%). A fully Bayesian analysis was undertaken in WinBUGS 1.4.3, first for a population pharmacokinetic (PK) analysis followed by a PKPD analysis. The developed PKPD model was used to predict the probability of having an abnormal QT as a surrogate for torsade de pointes. RESULTS A one compartment model with first order input and first-order elimination described the PK data, including uncertainty in dose and a baseline concentration for patients taking escitalopram therapeutically. SDAC reduced the fraction absorbed by 31% and reduced the individual predicted area under the curve adjusted for dose (AUCi/dose). The absolute QT interval was related to the observed heart rate with an estimated individual heart rate correction factor (α = 0.35). The heart rate corrected QT interval (QTc) was linearly dependent on predicted escitalopram concentration [slope = 87 ms/(mg l–1)], using a hypothetical effect-compartment (half-life of effect-delay, 1.0h). Administration of SDAC significantly reduced QT prolongation and was shown to reduce the risk of having an abnormal QT by approximately 35% for escitalopram doses above 200 mg. CONCLUSIONS There was a dose-related lengthening of the QT interval that lagged the increase in drug concentration. SDAC resulted in a moderate reduction in fraction of escitalopram absorbed and reduced the risk of the QT interval being abnormal. PMID:21883384

Electrocardiographic predictors of adverse cardiovascular events in suspected poisoning.

PubMed

Manini, Alex F; Nelson, Lewis S; Skolnick, Adam H; Slater, William; Hoffman, Robert S

2010-06-01

Poisoning is the second leading cause of injury-related fatality in the USA and the leading cause of cardiac arrest in victims under 40 years of age. The study objective was to define the electrocardiographic (ECG) predictors of adverse cardiovascular events (ACVE) complicating suspected acute poisoning (SAP). This was a case-control study in adults at three tertiary-care hospitals and one regional Poison Control Center. We compared 34 cases of SAP complicated by ACVE to 101 consecutive control patients with uncomplicated SAP. The initial ECG was analyzed for rhythm, intervals, QT dispersion, ischemia, and infarction. ECGs were interpreted by a cardiologist, blinded to study hypothesis and case data. Subjects were 48% male, with mean age 42 +/- 19 years. In addition to clinical suspicion of poisoning in 100% of patients, routine toxicology screens were positive in 77%, most commonly for benzodiazepines, opioids, and/or acetaminophen. Neither the ventricular rate, the QRS duration, nor the presence of infarction predicted the risk of ACVE. However, the rhythm, QTc, QT dispersion, and presence of ischemia correlated with the risk of ACVE. Independent predictors of ACVE based on multivariable logistic regression were prolonged QTc, any non-sinus rhythm, ventricular ectopy, and ischemia. Recursive partitioning analysis identified very low risk criteria (94.1% sensitivity, 96.2% NPV) and high risk criteria (95% specificity). Among patients with SAP, the presence of QTc prolongation, QT dispersion, ventricular ectopy, any non-sinus rhythm, and evidence of ischemia on the initial ECG are strongly associated with ACVE.

T-wave alternans and dispersion of the QT interval as risk stratification markers in patients susceptible to sustained ventricular arrhythmias

NASA Technical Reports Server (NTRS)

Armoundas, A. A.; Osaka, M.; Mela, T.; Rosenbaum, D. S.; Ruskin, J. N.; Garan, H.; Cohen, R. J.

1998-01-01

T-wave alternans and QT dispersion were compared as predictors of the outcome of electrophysiologic study and arrhythmia-free survival in patients undergoing electrophysiologic evaluation. T-wave alternans was a highly significant predictor of these 2 outcome variables, whereas QT dispersion was not.

Characterization of QT and RR interval series during acute myocardial ischemia by means of recurrence quantification analysis.

PubMed

Peng, Yi; Sun, Zhongwei

2011-01-01

This study is aimed to investigate the nonlinear dynamic properties of the fluctuations in ventricular repolarization, heart rate and their correlation during acute myocardial ischemia. From 13 ECG records in long-term ST-T database, 170 ischemic episodes were selected with the duration of 34 s to 23 min 18 s, and two 5-min episodes immediately before and after each ischemic episode as non-ischemic ones for comparison. QT interval (QTI) and RR interval (RRI) were extracted and the ectopic beats were removed. Recurrence quantification analysis (RQA) was performed on QTI and RRI series, respectively, and cross recurrence quantification analysis (CRQA) on paired normalized QTI and RRI series. Wilcoxon signed-rank test was used for statistical analysis. Results revealed that the RQA indexes for QTI and HRI series had the same changing trend during ischemia with more significantly changed indexes in QTI series. In the CRQA, indexes related to the vertical and horizontal structures in recurrence plot significantly increased, representing decreased dependency of QTI on RRI. Both QTI and RRI series showed reduced complexity during ischemia with higher sensitivity in ventricular repolarization. The weakened coupling between QTI and RRI suggests the decreased influence of sinoatrial node on QTI modulation during ischemia.

Usefulness of simultaneous and sequential monitoring of glucose level and electrocardiogram in monkeys treated with gatifloxacin under conscious and nonrestricted conditions.

PubMed

Yoshimatsu, Yu; Ishizaka, Tomomichi; Chiba, Katsuyoshi; Mori, Kazuhiko

2018-05-10

Drug-induced cardiac electrophysiological abnormalities accompanied by hypoglycemia or hyperglycemia increase the risk for life-threatening arrhythmia. To assess the drug-induced cardiotoxic potential associated with extraordinary blood glucose (GLU) levels, the effect of gatifloxacin (GFLX) which was frequently associated with GLU abnormality and QT/QTc prolongations in the clinic on blood GLU and electrocardiogram (ECG) parameters was investigated in cynomolgus monkeys (n=4) given GFLX orally in an ascending dose regimen (10, 30, 60 and 100 mg/kg). Simultaneous and sequential GLU and ECG monitoring with a continuous GLU monitoring system and Holter ECG, respectively, were conducted for 24 h under free-moving conditions. Consequently, GFLX at 30 and 60 mg/kg dose-dependently induced a transient decrease in GLU without any ECG abnormality 2-4 h postdose. Highest dose of 100 mg/kg caused severe hypoglycemia with a mean GLU of <30 mg/dL, accompanied by remarkable QT/QTc prolongations by 20-30% in all animals. In contrast, hyperglycemia without QT/QTc prolongations was noted 24 h after dosing in one animal. A close correlation between GLU and QTc values was observed in animals treated with 100 mg/kg, suggesting that GFLX-induced hypoglycemia enhanced QT/QTc prolongations. Furthermore, the 24-h sequential GLU monitoring data clearly distinguished between GFLX-induced GLU abnormality and physiological GLU changes influenced by feeding throughout the day. In conclusion, the combined assessment of continuous GLU and ECG monitoring is valuable in predicting the drug-induced cardio-electrophysiological risk associated with both GLU and ECG abnormalities.

[Long QT syndrome. History, genetics, clinical symptoms, causes and therapy].

PubMed

Krönauer, T; Friederich, P

2015-08-01

The long QT syndrome is caused by a change in cardiac repolarization due to functional ion channel defects. A differentiation is made between a congenital (cLQTS) and an acquired (aLQTS) form of the disease. The disease results in the name-giving prolongation of the QT interval in the electrocardiogram and represents a predisposition for cardiac arrhythmia and sudden cardiac death. This article summarizes the current knowledge on the history, pathophysiology, clinical symptoms and therapy of cLQTS and aLQTS. This knowledge of pathophysiological features of the symptoms allows the underlying anesthesiological approach for individualized perioperative concepts for patients suffering from LQTS to be derived.

Availability of human induced pluripotent stem cell-derived cardiomyocytes in assessment of drug potential for QT prolongation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nozaki, Yumiko, E-mail: yumiko-nozaki@ds-pharma.co.jp; Honda, Yayoi, E-mail: yayoi-honda@ds-pharma.co.jp; Tsujimoto, Shinji, E-mail: shinji-tsujimoto@ds-pharma.co.jp

2014-07-01

Field potential duration (FPD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs), which can express QT interval in an electrocardiogram, is reported to be a useful tool to predict K{sup +} channel and Ca{sup 2+} channel blocker effects on QT interval. However, there is no report showing that this technique can be used to predict multichannel blocker potential for QT prolongation. The aim of this study is to show that FPD from MEA (Multielectrode array) of hiPS-CMs can detect QT prolongation induced by multichannel blockers. hiPS-CMs were seeded onto MEA and FPD was measured for 2 min every 10 min formore » 30 min after drug exposure for the vehicle and each drug concentration. I{sub Kr} and I{sub Ks} blockers concentration-dependently prolonged corrected FPD (FPDc), whereas Ca{sup 2+} channel blockers concentration-dependently shortened FPDc. Also, the multichannel blockers Amiodarone, Paroxetine, Terfenadine and Citalopram prolonged FPDc in a concentration dependent manner. Finally, the I{sub Kr} blockers, Terfenadine and Citalopram, which are reported to cause Torsade de Pointes (TdP) in clinical practice, produced early afterdepolarization (EAD). hiPS-CMs using MEA system and FPDc can predict the effects of drug candidates on QT interval. This study also shows that this assay can help detect EAD for drugs with TdP potential. - Highlights: • We focused on hiPS-CMs to replace in vitro assays in preclinical screening studies. • hiPS-CMs FPD is useful as an indicator to predict drug potential for QT prolongation. • MEA assay can help detect EAD for drugs with TdP potentials. • MEA assay in hiPS-CMs is useful for accurately predicting drug TdP risk in humans.« less

Cardiac and non-cardiac causes of T-wave inversion in the precordial leads in adult subjects: A Dutch case series and review of the literature

PubMed Central

Said, Salah AM; Bloo, Rene; de Nooijer, Ramon; Slootweg, Andries

2015-01-01

AIM: To describe the electrocardiographic (ECG) phenomena characterized by T-wave inversion in the precordial leads in adults and to highlight its differential diagnosis. METHODS: A retrospective chart review of 8 adult patients who were admitted with ECG T-wave inversion in the anterior chest leads with or without prolongation of corrected QT (QTc) interval. They had different clinical conditions. Each patient underwent appropriate clinical assessment including investigation for myocardial involvement. Single and multimodality non-invasive, semi-invasive and invasive diagnostic approach were used to ascertain the diagnosis. The diagnostic assessment included biochemical investigation, cardiac and abdominal ultrasound, cerebral and chest computed tomography, nuclear medicine and coronary angiography. RESULTS: Eight adult subjects (5 females) with a mean age of 66 years (range 51 to 82) are analyzed. The etiology of T-wave inversion in the precordial leads were diverse. On admission, all patients had normal blood pressure and the ECG showed sinus rhythm. Five patients showed marked prolongation of the QTc interval. The longest QTc interval (639 ms) was found in the patient with pheochromocytoma. Giant T-wave inversion (≥ 10 mm) was found in pheochromocytoma followed by electroconvulsive therapy and finally ischemic heart disease. The deepest T-wave was measured in lead V3 (5 ×). In 3 patients presented with mild T-wave inversion (patients 1, 5 and 4 mm), the QTc interval was not prolonged (432, 409 and 424 msec), respectively. CONCLUSION: T-wave inversion associated with or without QTc prolongation requires meticulous history taking, physical examination and tailored diagnostic modalities to reach rapid and correct diagnosis to establish appropriate therapeutic intervention. PMID:25717356

Long QT syndrome and sudden unexpected infant death.

PubMed

Van Niekerk, Chantal; Van Deventer, Barbara Ströh; du Toit-Prinsloo, Lorraine

2017-09-01

Long QT syndrome (LQTS) is an inheritable primary electric disease of the heart characterised by abnormally long QT intervals and a propensity to develop atrial and ventricular tachyarrhythmias. It is caused by an inherited channelopathy responsible for sudden cardiac death in individuals with structurally normal hearts. Long QT syndrome can present early in life, and some studies suggest that it may be associated with up to 20% of sudden unexplained infant death (SUID), particularly when associated with external stressors such as asphyxia, which is commonly seen in many infant death scenes. With an understanding of the genetic defects, it has now been possible to retrospectively analyse samples from infants who have presented to forensic pathology services with a history of unexplained sudden death, which may, in turn, enable the implementation of preventative treatment for siblings previously not known to have pathogenic genetic variations. In this viewpoint article, we will discuss SUID, LQTS and postmortem genetic analysis. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant.

PubMed

Lane, Conor; Giudicessi, John R; Ye, Dan; Tester, David J; Rohatgi, Ram K; Bos, J Martijn; Ackerman, Michael J

2018-04-03

Long QT syndrome (LQTS) genetic test reports commonly exclude potentially proarrhythmic common variants such as p.Asp85Asn-KCNE1. The purpose of this study was to determine whether a discernible phenotype is associated with p.Asp85Asn-KCNE1 and whether relatively common KCNE1 variants underlie transient QT prolongation pedigrees with negative commercial LQTS genetic tests. Retrospective review was used to compare demographics, symptomatology, and QT parameters of individuals with p.Asp85Asn-KCNE1 in the absence of other rare/ultra-rare variants in LQTS-susceptibility genes and those who underwent comprehensive LQTS genetic testing. Compared to the Genome Aggregation Database, p.Asp85Asn-KCNE1 was more prevalent in individuals undergoing LQTS genetic testing (33/1248 [2.6%] vs 1552/126,652 [1.2%]; P = .0001). In 19 of 33 patients (58%), only p.Asp85Asn-KCNE1 was observed. These patients were predominantly female (90% vs 62%; P = .02) and were less likely to experience syncope (0% vs 34%; P = .0007), receive β-blockers (53% vs 85%; P = .001), or require an implantable cardioverter-defibrillator (5.3% vs 33%; P = .01). However, they exhibited a similar degree of QT prolongation (QTc 460 ms vs 467 ms; P = NS). Whole exome sequencing of 2 commercially genotype-negative pedigrees revealed that p.Asp85Asn-KCNE1 and p.Arg36His-KCNE1 traced with a transient QT prolongation phenotype. Functional characterization of p.Arg36His-KCNE1 demonstrated loss of function, with a 47% reduction in peak I Ks current density in the heterozygous state. We provide further evidence that relatively common variants in KCNE1 may result in a mild QT phenotype designated as "LQT5-Lite" to distinguish such potentially proarrhythmic common variants (ie, functional risk alleles) from rare pathogenic variants that truly confer monogenic disease susceptibility, albeit with incomplete penetrance. Copyright © 2018. Published by Elsevier Inc.

Method for Correction of Consequences of Radiation-Induced Heart Disease using Low-Intensity Electromagnetic Emission under Experimental Conditions.

PubMed

Bavrina, A P; Monich, V A; Malinovskaya, S L; Yakovleva, E I; Bugrova, M L; Lazukin, V F

2015-05-01

Effects of successive exposure to ionizing irradiation and low-intensity broadband red light on electrical activity of the heart and myocardium microstructure were studied in rats. Lowintensity red light corrected some ECG parameters, in particular, it normalized QT and QTc intervals and voltage of R and T waves. Changes in ECG parameters were followed by alterations in microstructure of muscle fi laments in the myocardium of treatment group animals comparing to control group.

Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes.

PubMed

Isbister, Geoffrey K; Balit, Corrine R; Macleod, Dawson; Duffull, Stephen B

2010-08-01

This study aimed to describe the effects of the antipsychotic amisulpride in overdose, including the frequency of QT prolongation and torsades de pointes. Cases of amisulpride overdose (>1 g) were recruited from 2 state poison centers and a tertiary toxicology unit over 5 years. A 1-page clinical research form was used to collect clinical information. Copies of all electrocardiograms were obtained. Electrocardiogram parameters (QRS and QT intervals) were manually measured as previously described, and plots of QT-heart rate (HR) pairs were compared with the QT nomogram. There were 83 patients with amisulpride overdoses with a median age of 29 years (interquartile range [IQR], 23-40 years), and 42 (51%) were female. The median dose ingested was 6 g (IQR, 3-13 g, range, 1.2-120 g). The median HR was 66 beats/min (IQR, 60-81 beats/min). Bradycardia occurred in 20 cases (24%), and hypotension in 19 (23%). From 440 electrocardiograms (average of 5 per case; range, 1-15), an abnormal QT-HR pair occurred in 61 cases (73%). Torsades de pointes developed in 6 cases (7%), with doses of 4, 4.6, 18, 24, 32, and 80 g. The patient taking 32 g died after a cardiac arrest. Widened QRS did not occur except transient rate-dependent bundle-branch block in 3 cases. There were significant associations of bradycardia, hypokalemia, and hypocalcaemia, with QT prolongation and torsades de pointes. Central nervous system effects were uncommon with coma in 7 cases, seizures in 2, and dystonic reactions in 2. Amisulpride overdose commonly causes QT prolongation, bradycardia, and hypotension. Torsades de pointes occurred commonly enough to suggest that amisulpride is highly cardiotoxic in overdose.

Upregulation of microRNA-1 and microRNA-133 contributes to arsenic-induced cardiac electrical remodeling.

PubMed

Shan, Hongli; Zhang, Yong; Cai, Benzhi; Chen, Xi; Fan, Yuhua; Yang, Lili; Chen, Xichuang; Liang, Haihai; Zhang, Ying; Song, Xiaohui; Xu, Chaoqian; Lu, Yanjie; Yang, Baofeng; Du, Zhimin

2013-09-10

A large body of evidence showed that arsenic trioxide (As2O3), a front-line drug for the treatment of acute promyelocytic leukemia, induced abnormal cardiac QT prolongation, which hampers its clinical use. The molecular mechanisms for this cardiotoxicity remained unclear. This study aimed to elucidate whether microRNAs (miRs) participate in As2O3-induced QT prolongation. A guinea pig model of As2O3-induced QT prolongation was established by intravenous injection with As2O3. Real-time PCR and Western blot were employed to determine the expression alterations of miRs and mRNAs, and their corresponding proteins. The QT interval and QRS complex were significantly prolonged in a dose-dependent fashion after 7-day administration of As2O3. As2O3 induced a significant upregulation of the muscle-specific miR-1 and miR-133, as well as their transactivator serum response factor. As2O3 depressed the protein levels of ether-a-go-go related gene (ERG) and Kir2.1, the K(+) channel subunits responsible for delayed rectifier K(+) current IKr and inward rectifier K(+) current IK1, respectively. In vivo transfer of miR-133 by direct intramuscular injection prolonged QTc interval and increased mortality rate, along with depression of ERG protein and IKr in guinea pig hearts. Similarly, forced expression of miR-1 widened QTc interval and QRS complex and increased mortality rate, accompanied by downregulation of Kir2.1 protein and IK1. Application of antisense inhibitors to knockdown miR-1 and miR-133 abolished the cardiac electrical disorders caused by As2O3. Deregulation of miR-133 and miR-1 underlies As2O3-induced cardiac electrical disorders and these miRs may serve as potential therapeutic targets for the handling of As2O3 cardiotoxicity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Assessments of the QT/QRS restitution in perfused guinea-pig heart can discriminate safe and arrhythmogenic drugs.

PubMed

Osadchii, Oleg E

2017-09-01

Drug-induced arrhythmia remains a matter of serious clinical concern, partly due to low prognostic value of currently available arrhythmic biomarkers. This study examined whether arrhythmogenic risks can be predicted through assessments of the rate adaptation of QT interval, ventricular effective refractory period (ERP), or the QT/QRS ratio, in perfused guinea-pig hearts. When the maximum restitution slope was taken as a metric of proarrhythmia, neither QT interval nor ERP measurements at progressively increased pacing rates were found to fully discriminate arrhythmogenic drugs (dofetilide, quinidine, flecainide, and procainamide) from those recognized as safe antiarrhythmics (lidocaine and mexiletine). For example, the slope of QT restitution was increased by dofetilide and quinidine, but remained unchanged by flecainide, procainamide, lidocaine, and mexiletine. With ERP rate adaptation, even though the restitution slope was increased by dofetilide, all class I agents reduced the slope value independently of their safety profile. The QRS measurements revealed variable drug effects, ranging from significant use-dependent conduction slowing (flecainide, quinidine, and procainamide) to only modest increase in QRS (lidocaine and mexiletine), or no change at all (dofetilide). However, with the QT/QRS rate adaptation, the restitution slope was significantly increased by all agents which have been reported to produce proarrhythmic effects (dofetilide, quinidine, flecainide, and procainamide), but not changed by lidocaine and mexiletine. These findings suggest that the slope of the QT/QRS rate adaptation can be considered as a novel electrophysiological biomarker in predicting potential arrhythmic risks associated with pharmacotherapy in cardiac patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Recent advances in understanding sex differences in cardiac repolarization.

PubMed

James, Andrew F; Choisy, Stéphanie C M; Hancox, Jules C

2007-07-01

A number of gender differences exist in the human electrocardiogram (ECG): the P-wave and P-R intervals are slightly longer in men than in women, whilst women have higher resting heart rates than do men, but a longer rate-corrected QT (QT(C)) interval. Women with the LQT1 and LQT2 variants of congenital long-QT syndrome (LQTS) are at greater risk of adverse cardiac events. Similarly, many drugs associated with acquired LQTS have a greater risk of inducing torsades de pointes (TdP) arrhythmia in women than in men. There are also male:female differences in Brugada syndrome, early repolarisation syndrome and sudden cardiac death. The differences in the ECG between men and women, and in particular those relating to the QT interval, have been explored experimentally and provide evidence of differences in the processes underlying ventricular repolarization. The data available from rabbit, canine, rat, mouse and guinea pig models are reviewed and highlight involvement of male:female differences in Ca and K currents, although the possible involvement of rapid and persistent Na current and Na-Ca exchange currents cannot yet be excluded. The mechanisms underlying observed differences remain to be elucidated fully, but are likely to involve the influence of gonadal steroids. With respect to the QT interval and risk of TdP, a range of evidence implicates a protective role of testosterone in male hearts, possibly by both genomic and non-genomic pathways. Evidence regarding oestrogen and progesterone is less unequivocal, although the interplay between these two hormones may influence both repolarization and pro-arrhythmic risk.

Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti-MRSA fluoroquinolone JNJ-Q2.

PubMed

Eichenbaum, G; Pugsley, M K; Gallacher, D J; Towart, R; McIntyre, G; Shukla, U; Davenport, J M; Lu, H R; Rohrbacher, J; Hillsamer, V

2012-07-01

JNJ-Q2, a novel broad-spectrum fluoroquinolone with anti-methicillin-resistant Staphylococcus aureus activity, was evaluated in a comprehensive set of non-clinical and clinical cardiovascular safety studies. The effect of JNJ-Q2 on different cardiovascular parameters was compared with that of moxifloxacin, sparfloxacin and ofloxacin. Through comparisons with these well-known fluoroquinolones, the importance of effects on compensatory ion channels to the cardiovascular safety of JNJ-Q2 was investigated. JNJ-Q2 and comparator fluoroquinolones were evaluated in the following models/test systems: hERG-transfected HEK293 cells sodium channel-transfected CHO cells, guinea pig right atria, arterially perfused rabbit left ventricular wedge preparations and in vivo studies in anaesthetized guinea pigs, anaesthetized and conscious telemetered dogs, and a thorough QT study in humans. The trend for effects of JNJ-Q2 on Tp-Te, QT, QRS and PR intervals in the non-clinical models and the plateau in QTc with increasing plasma concentration in humans are consistent with offsetting sodium and calcium channel activities that were observed in the non-clinical studies. These mixed ion channel activities result in the less pronounced or comparable increase in QTc interval for JNJ-Q2 compared with moxifloxacin and sparfloxacin despite its greater in vitro inhibition of I(Kr). Based on the non-clinical and clinical cardiovascular safety assessment, JNJ-Q2 has a safe cardiovascular profile for administration in humans with comparable or reduced potential to prolong QT intervals, compared with moxifloxacin. The results demonstrate the importance of compensatory sodium and calcium channel activity in offsetting potassium channel activity for compounds with a fluoroquinolone core. © 2012 Janssen Pharmaceutical Companies of Johnson & Johnson. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Association of Serum Magnesium on Mortality in Patients Admitted to the Intensive Cardiac Care Unit.

PubMed

Naksuk, Niyada; Hu, Tiffany; Krittanawong, Chayakrit; Thongprayoon, Charat; Sharma, Sunita; Park, Jae Yoon; Rosenbaum, Andrew N; Gaba, Prakriti; Killu, Ammar M; Sugrue, Alan M; Peeraphatdit, Thoetchai; Herasevich, Vitaly; Bell, Malcolm R; Brady, Peter A; Kapa, Suraj; Asirvatham, Samuel J

2017-02-01

Although electrolyte disturbances may affect cardiac action potential, little is known about the association between serum magnesium and corrected QT (QTc) interval as well as clinical outcomes. A consecutive 8498 patients admitted to the Mayo Clinic Hospital-Rochester cardiac care unit (CCU) from January 1, 2004 through December 31, 2013 with 2 or more documented serum magnesium levels, were studied to test the hypothesis that serum magnesium levels are associated with in-hospital mortality, sudden cardiac death, and QTc interval. Patients were 67 ± 15 years; 62.2% were male. The primary diagnoses for CCU admissions were acute myocardial infarction (50.7%) and acute decompensated heart failure (42.5%), respectively. Patients with higher magnesium levels were older, more likely male, and had lower glomerular filtration rates. After multivariate analyses adjusted for clinical characteristics including kidney disease and serum potassium, admission serum magnesium levels were not associated with QTc interval or sudden cardiac death. However, the admission magnesium levels ≥2.4 mg/dL were independently associated with an increase in mortality when compared with the reference level (2.0 to <2.2 mg/dL), having an adjusted odds ratio of 1.80 and a 95% confidence interval of 1.25-2.59. The sensitivity analysis examining the association between postadmission magnesium and analysis that excluded patients with kidney failure and those with abnormal serum potassium yielded similar results. This retrospective study unexpectedly observed no association between serum magnesium levels and QTc interval or sudden cardiac death. However, serum magnesium ≥2.4 mg/dL was an independent predictor of increased hospital morality among CCU patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Effect of nicorandil on QT dispersion in patients with stable angina pectoris undergoing elective angioplasty: A triple-blind, randomized, placebo-controlled study

PubMed Central

Suleimani, Homa Fal; Eshraghi, Ali; Daloee, Mehdi Hasanzadeh; Hoseini, Sara; Nakhaee, Nima

2017-01-01

Background Nicorandil leads to the relaxation of fine vascular smooth muscle, and thus causes vasodilatation of major epicardial. Also, it has anti-arrhythmic and cardio-protective effects by improving reperfusion, and ultimately leads to a reduction in microvascular damage caused by percutaneous coronary intervention (PCI). Objective The aim of this study was to determine the effect of nicorandil on QT interval dispersion (QTd) in patients with stable angina pectoris during elective angioplasty. Methods This triple-blind and randomized clinical trial was performed on patients with stable angina pectoris, candidates for elective angiography referred to Imam Reza and Ghaem hospitals in Mashhad, Iran, between January and October 2016. The patients were randomly assigned to one of two groups receiving nicorandil (60 mg as 20 mg before and 40 mg after PCI) and placebo. All the patients underwent electrocardiography 12 hours before and 12 hours after PCI. The values of maximal corrected QT interval (QTc max) and QTd in these intervals, and the levels of changes in the QTd (QTd difference before angiography and after PCI) were compared between the two groups. Data were analyzed statistically using SPSS version 18 software via Chi-square and Independent-samples t-test. Results This study was performed on 90 patients (55 males and 35 females) with a mean age of 58.6±10.8 years, on two groups of 45 people. The two groups were matched for age, body mass index, cardiovascular risk factors and baseline testing. The QTd before angiography had no statistically significant difference between the patients of both groups (control: 77.7±17.1 vs. nicorandil: 80.7±14.2 ms; p=0.371). The QTd after PCI in the nicorandil group was lower than the control group (48.1±14.2 vs. 59.2±15.6 ms; p=0.000). The decrease rate in QTd had a statistically significant difference between the two groups (control: 18.9±11.0 vs. nicorandil: 33.5±9.5 ms; p=0.000). Conclusions The results of this

ECG Changes in Young Healthy Smokers: A Simple and Cost-Effective Method to Assess Cardiovascular Risk According to Pack-Years of Smoking.

PubMed

Sharma, Nirmal Kumar; Jaiswal, Kapil Kumar; Meena, S R; Chandel, Rahul; Chittora, Saurabh; Goga, Prem Singh; Harish, H B; Sagar, Rajesh

2017-06-01

To document the prevalence of ECG abnormalities in young healthy smokers and compare ECG changes in smokers, young healthy non-smokers and amongst smokers with different pack years. This was a prospective case-control study consisting of 200 young healthy male and female individuals, 150 smokers and 50 non-smokers between ages 25-40 years, further categorized and compared according to age, sex and pack years of smoking. The ECG recordings were analyzed for different ECG parameters like heart rate, P-wave duration, P-wave amplitude, PR interval, QRS duration, RR-interval, ST-segment duration, QT interval and QTc interval. The results were compared using statistical tools. In present study abnormalities in ECG parameters were significantly more prevalent in smokers as compared to non-smokers (56.66 % Vs 6.00 %) (p <.0001). Heart rate and QTc-interval increased with increase in the number of pack-years. This increase was reflected more in female with a similar number of pack years. P-wave amplitude tended to increase with increase in the number of pack years more so in males. P-wave duration, PR-interval, QRS-duration and RR-interval tended to decrease with increase in the number of pack years more so in females with similar number of pack years. QT-interval and ST-segment duration tended to decrease with increase in the number of pack years more so in males. ECG abnormalities in this study indicate cardiovascular risk in term of cardiac arrhythmia, pulmonary arterial hypertension, heart blocks etc in such subjects. As this procedure is non-invasive and cost effective it is potentially an effective and yet a simple method for cardiovascular risk evaluation in smokers. Furthermore, such ECG abnormalities may guide the clinician for risk evaluation in smokers and may be used to convince the smokers to quit smoking.

Effect of valsartan on cardiac senescence and apoptosis in a rat model of cardiotoxicity.

PubMed

Sakr, Hussein F; Abbas, Amr M; Elsamanoudy, Ayman Z

2016-06-01

The clinical application of doxorubicin is limited by its cardiotoxicity. The present study investigated the effect of valsartan on doxorubicin-induced cardiotoxicity in rats. Rats were divided into 6 groups: control, control + valsartan (10 mg/kg, for 14 days, orally), doxorubicin-treated (2.5 mg/kg, 3 times/week for 2 weeks, intraperitoneally), valsartan then doxorubicin, valsartan + doxorubicin, and doxorubicin then valsartan. ECG, isolated heart, lipid peroxidation (thiobaribituric acid reactive substances (TBARS)), total antioxidant capacity (TAC), and Bax, Bcl-2, and senescence marker protein 30 (SMP30) gene expression were measured in cardiac tissue. Blood samples were collected to measure lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB). Doxorubicin significantly increased LDH, CK-MB, TBARS, heart rate (HR), Bax gene expression, and -dP/dtmax and decreased TAC, Bcl-2 and SMP30 gene expression, left ventricular developed pressure (LVDP), and +dP/dtmax. Also, doxorubicin lengthened ST, QT, and QTc intervals. Concurrent or post- but not pre-treatment of doxorubicin-treated rats with valsartan reduced LDH, CK-MB, TBARS, HR, Bax gene expression, -dP/dtmax, and ST, QT, and QTc intervals and increased TAC, Bcl-2 and SMP30 gene expression, LVDP, and +dP/dtmax. Therefore, we conclude that concurrent or post- but not pre-treatment of doxorubicin-induced rats with valsartan attenuated doxorubicin-induced cardiotoxicity through inhibiting oxidative stress, apoptosis, and senescence.

Graphical representation of QT rate correction formulae: an aid facilitating the use of a given formula and providing a visual comparison of the impact of different formulae.

PubMed

Rowlands, Derek J

2012-01-01

The QT interval on the electrocardiogram is an increasingly important measurement, especially in relation to drug action and interaction. The QT interval varies inversely as the heart rate and numerous rate correction formulae have been proposed. It is difficult to compare the effect of applying different formulae at different heart rates and for different measured QT intervals. A simple graphical display of the results from different formulae is proposed. This display is dependent on the concept of the absolute correction factor. This graphical presentation is useful (a) in comparing the effect of the application of different formulae and (b) in directly reading the correction produced by any individual formula. Copyright © 2012 Elsevier Inc. All rights reserved.

Pharmacokinetics and repolarization effects of intravenous and transdermal granisetron.

PubMed

Mason, Jay W; Selness, Daniel S; Moon, Thomas E; O'Mahony, Bridget; Donachie, Peter; Howell, Julian

2012-05-15

The need for greater clarity about the effects of 5-HT(3) receptor antagonists on cardiac repolarization is apparent in the changing product labeling across this therapeutic class. This study assessed the repolarization effects of granisetron, a 5-HT(3) receptor antagonist antiemetic, administered intravenously and by a granisetron transdermal system (GTDS). In a parallel four-arm study, healthy subjects were randomized to receive intravenous granisetron, GTDS, placebo, or oral moxifloxacin (active control). The primary endpoint was difference in change from baseline in mean Fridericia-corrected QT interval (QTcF) between GTDS and placebo (ddQTcF) on days 3 and 5. A total of 240 subjects were enrolled, 60 in each group. Adequate sensitivity for detection of QTc change was shown by a 5.75 ms lower bound of the 90% confidence interval (CI) for moxifloxacin versus placebo at 2 hours postdose on day 3. Day 3 ddQTcF values varied between 0.2 and 1.9 ms for GTDS (maximum upper bound of 90% CI, 6.88 ms), between -1.2 and 1.6 ms for i.v. granisetron (maximum upper bound of 90% CI, 5.86 ms), and between -3.4 and 4.7 ms for moxifloxacin (maximum upper bound of 90% CI, 13.45 ms). Day 5 findings were similar. Pharmacokinetic-ddQTcF modeling showed a minimally positive slope of 0.157 ms/(ng/mL), but a very low correlation (r = 0.090). GTDS was not associated with statistically or clinically significant effects on QTcF or other electrocardiographic variables. This study provides useful clarification on the effect of granisetron delivered by GTDS on cardiac repolarization. ©2012 AACR.

Behavioral Hyperventilation and Central Sleep Apnea in Two Children

PubMed Central

Johnston, Thomas P.; Tam-Williams, Jade; Schmandt, Margaret; Patel, Anand C.; Cleveland, Claudia; Coste, Ferdinand; Kemp, James S.

2015-01-01

Behavioral hyperventilation is a rarely recognized cause of central sleep apnea (CSA) among children. We report two pediatric patients who presented with prolonged central sleep apnea secondary to behavioral hyperventilation. One patient also had a prolonged corrected QT (QTC) interval resulting from hyperventilation. Citation: Johnston TP, Tam-Williams J, Schmandt M, Patel AC, Cleveland C, Coste F, Kemp JS. Behavioral hyperventilation and central sleep apnea in two children. J Clin Sleep Med 2015;11(4):487–489. PMID:26106657

Risk of cardiac events in Long QT syndrome patients when taking antiseizure medications.

PubMed

Auerbach, David S; Biton, Yitschak; Polonsky, Bronislava; McNitt, Scott; Gross, Robert A; Dirksen, Robert T; Moss, Arthur J

2018-01-01

Many antiseizure medications (ASMs) affect ion channel function. We investigated whether ASMs alter the risk of cardiac events in patients with corrected QT (QT c ) prolongation. The study included people from the Rochester-based Long QT syndrome (LQTS) Registry with baseline QT c prolongation and history of ASM therapy (n = 296). Using multivariate Anderson-Gill models, we assessed the risk of recurrent cardiac events associated with ASM therapy. We stratified by LQTS genotype and predominant mechanism of ASM action (Na + channel blocker and gamma-aminobutyric acid modifier.) There was an increased risk of cardiac events when participants with QT c prolongation were taking vs off ASMs (HR 1.65, 95% confidence interval [CI] 1.36-2.00, P < 0.001). There was an increased risk of cardiac events when LQTS2 (HR 1.49, 95% CI 1.03-2.15, P = 0.036) but not LQTS1 participants were taking ASMs (interaction, P = 0.016). Na + channel blocker ASMs were associated with an increased risk of cardiac events in participants with QT c prolongation, specifically LQTS2, but decreased risk in LQTS1. The increased risk when taking all ASMs and Na + channel blocker ASMs was attenuated by concurrent beta-adrenergic blocker therapy (interaction, P < 0.001). Gamma-aminobutyric acid modifier ASMs were associated with an increased risk of events in patients not concurrently treated with beta-adrenergic blockers. Female participants were at an increased risk of cardiac events while taking all ASMs and each class of ASMs. Despite no change in overall QT c duration, pharmacogenomic analyses set the stage for future prospective clinical and mechanistic studies to validate that ASMs with predominantly Na + channel blocking actions are deleterious in LQTS2, but protective in LQTS1. Copyright © 2017 Elsevier Inc. All rights reserved.

Central aortic systolic blood pressure can predict prolonged QTc duration better than brachial artery systolic blood pressure in rural community residents.

PubMed

Huang, Yuqing; Tang, Songtao; Chen, Ji-Yan; Huang, Cheng; Li, Jie; Cai, An-Ping; Feng, Yingqing

2018-01-01

Previous studies have suggested that prolonged electrocardiogram QTc duration was independent risk factor for both increased cardiovascular and all-cause mortality, but there was no dating about the relationship between central aortic systolic blood pressure (CASP) and QTc duration. The aim of this study was to analyze the relationship between CASP and QTc duration, and assess whether CASP can predict prolonged QTc duration more than BSBP. A total of 500 patients were enrolled in this study, central and brachial aortic blood pressure and electrocardiogram QTc duration were measured. Pearson correlation was assessed for determining the associations of QTc duration with clinical conditions. Multivariate logistic regression analyses were performed to determine the independent predictor of prolonged QTc duration. Receiver operating characteristic (ROC) curve was used to evaluate the utility of blood pressure for prolonged QTc duration. We found QTc durations were significantly positive with CASP (r = 0.308, p < 0.001), BSBP (r = 0.227, p < 0.001), and age (r = 0.154, p = 0.010), but negatively related to heart rate (r = -440, p < 0.001). A multiple logistic regression analysis demonstrated that the CASP was an independent determinant of prolonged QTc (OR = 1.648; 95%CI: 1.032, 2.101; p < 0.001). CASP had a better predictive value for prolonged QTc duration than (AUC: 0.771 vs. 0.646, p < 0.001) BSBP. Our results suggested that the non-invasive CASP is independently correlated with QTc duration, and CASP can predict prolonged QTc duration more than BSBP.

Potassium channel KCNH2 K897T polymorphism and cardiac repolarization during exercise test: The Finnish Cardiovascular Study.

PubMed

Koskela, J; Laiho, J; KäHönen, M; Rontu, R; Lehtinen, R; Viik, J; Niemi, M; Niemelä, K; Kööbi, T; Turjanmaa, V; Pörsti, I; Lehtimäki, T; Nieminen, T

2008-01-01

Cardiac repolarization is regulated, in part, by the KCNH2 gene, which encodes a rapidly activating component of the delayed rectifier potassium channel. The gene expresses a functional single nucleotide polymorphism, K897T, which changes the biophysical properties of the channel. The objective of this study was to evaluate whether this polymorphism influences two indices of repolarization--the QT interval and T-wave alternans (TWA)--during different phases of a physical exercise test. The cohort consisted of 1,975 patients undergoing an exercise test during which on-line electrocardiographic data were registered. Information on coronary risk factors and medication was recorded. The 2690A>C nucleotide variation in the KCNH2 gene corresponding to the K897T amino acid change was analysed after polymerase chain reaction with allele-specific TaqMan probes. Among all subjects, the QTc intervals did not differ between the three genotype groups (p> or =0.31, RANOVA). Women with the CC genotype tended to have longer QT intervals during the exercise test, but the difference was statistically significant only at rest (p = 0.011, ANOVA). This difference was also detected when the analysis was adjusted for several factors influencing the QT interval. No statistically significant effects of the K897T polymorphism on TWA were observed among all subjects (p = 0.16, RANOVA), nor in men and women separately. The K897T polymorphism of the KCNH2 gene may not be a major genetic determinant for the TWA, but the influence of the CC genotype on QT interval deserves further research among women.

Treatment of cardiac arrhythmias in a mouse model of Rett syndrome with Na+-channel-blocking antiepileptic drugs

PubMed Central

Herrera, José A.; Ward, Christopher S.; Pitcher, Meagan R.; Percy, Alan K.; Skinner, Steven; Kaufmann, Walter E.; Glaze, Daniel G.; Wehrens, Xander H. T.; Neul, Jeffrey L.

2015-01-01

One quarter of deaths associated with Rett syndrome (RTT), an X-linked neurodevelopmental disorder, are sudden and unexpected. RTT is associated with prolonged QTc interval (LQT), and LQT-associated cardiac arrhythmias are a potential cause of unexpected death. The standard of care for LQT in RTT is treatment with β-adrenergic antagonists; however, recent work indicates that acute treatment of mice with RTT with a β-antagonist, propranolol, does not prevent lethal arrhythmias. In contrast, acute treatment with the Na+ channel blocker phenytoin prevented arrhythmias. Chronic dosing of propranolol may be required for efficacy; therefore, we tested the efficacy of chronic treatment with either propranolol or phenytoin on RTT mice. Phenytoin completely abolished arrhythmias, whereas propranolol showed no benefit. Surprisingly, phenytoin also normalized weight and activity, but worsened breathing patterns. To explore the role of Na+ channel blockers on QT in people with RTT, we performed a retrospective analysis of QT status before and after Na+ channel blocker antiepileptic therapies. Individuals with RTT and LQT significantly improved their QT interval status after being started on Na+ channel blocker antiepileptic therapies. Thus, Na+ channel blockers should be considered for the clinical management of LQT in individuals with RTT. PMID:25713300

Multi-channel System for Beat to Beat QT Interval Variability and its Use in Screening for Coronary Artery Disease and Cardiomyopathy

NASA Technical Reports Server (NTRS)

Starc, V.; Schlegel, T. T.; Arenare, B.; Greco, E. C.; DePalma, J. L.; Nunez, T.; Medina, R.; Jugo, D.; Rahman, M. A.; Delgado, R.

2007-01-01

We investigated the ability of beat-to-beat QT interval variability (QTV) and related parameters to differentiate healthy individuals from patients with obstructive coronary artery disease (CAD) and cardiomyopathy (CM). For this purpose we developed a PC-based ECG software program that in real time, acquires, analyzes and displays QTV in each of the eight independent channels that constitute the 12-lead conventional ECG. The system also analyzes and displays the QTV from QT interval signals that are derived from multiple channels and from singular value decomposition (SVD) to substantially reduce the effect of noise and other artifacts on the QTV results. It also provides other useful SVD-related parameters such as the normalized 3-dimensional volume of the T wave (nTV) = 100*(rho(sub 2)*rho(sub 3)rho(sub 1^2). Advanced high-fidelity 12-lead ECG tests (approx. 5-min supine) were first performed on a "training set" of 99 individuals: 33 with ischemic or dilated CM and low ejection fraction (EF less than 40%); 33 with catheterization-proven obstructive CAD but normal EF; and 33 age-/gender-matched healthy controls. All QTV parameters that were studied for their accuracy in detecting CM and CAD significantly differentiated both CM and CAD from controls (p less than 0.0001). Retrospective areas under the ROC curve (AUC) of SDNN-QTV, rmsSD-QTV, and QTV Index (QTVI) for CM vs. controls in the lead V5 were 0.85, 0.90, and 0.99, respectively, and those for CAD vs. controls in the lead II were 0.82, 0.82, and 0.89. Other advanced ECG parameters, such as HFQRS RAZ score, LF Lomb of RRV or QRS-T angle, differentiated both CM and CAD from controls less significantly, with the respective AUC values of 0.89, 0.88 and 0.98 for CM vs. controls, and 0.73, 0.71 and 0.80 for CAD vs. controls. QTV parameters (especially QTVI, which is QTV as indexed to RRV) were, diagnostically speaking, amongst the best performing of the advanced ECG techniques studied thus far.

Leptin decreases heart rate associated with increased ventricular repolarization via its receptor.

PubMed

Lin, Yen-Chang; Huang, Jianying; Hileman, Stan; Martin, Karen H; Hull, Robert; Davis, Mary; Yu, Han-Gang

2015-11-15

Leptin has been proposed to modulate cardiac electrical properties via β-adrenergic receptor activation. The presence of leptin receptors and adipocytes in myocardium raised a question as to whether leptin can directly modulate cardiac electrical properties such as heart rate and QT interval via its receptor. In this work, the role of local direct actions of leptin on heart rate and ventricular repolarization was investigated. We identified the protein expression of leptin receptors at cell surface of sinus node, atrial, and ventricular myocytes isolated from rat heart. Leptin at low doses (0.1-30 μg/kg) decreased resting heart rate; at high doses (150-300 μg/kg), leptin induced a biphasic effect (decrease and then increase) on heart rate. In the presence of high-dose propranolol (30 mg/kg), high-dose leptin only reduced heart rate and sometimes caused sinus pauses and ventricular tachycardia. The leptin-induced inhibition of resting heart rate was fully reversed by leptin antagonist. Leptin also increased heart rate-corrected QT interval (QTc), and leptin antagonist did not. In isolated ventricular myocytes, leptin (0.03-0.3 μg/ml) reversibly increased the action potential duration. These results supported our hypothesis that in addition to indirect pathway via sympathetic tone, leptin can directly decrease heart rate and increase QT interval via its receptor independent of β-adrenergic receptor stimulation. During inhibition of β-adrenergic receptor activity, high concentration of leptin in myocardium can cause deep bradycardia, prolonged QT interval, and ventricular arrhythmias. Copyright © 2015 the American Physiological Society.

Leptin decreases heart rate associated with increased ventricular repolarization via its receptor

PubMed Central

Lin, Yen-Chang; Huang, Jianying; Hileman, Stan; Martin, Karen H.; Hull, Robert; Davis, Mary

2015-01-01

Leptin has been proposed to modulate cardiac electrical properties via β-adrenergic receptor activation. The presence of leptin receptors and adipocytes in myocardium raised a question as to whether leptin can directly modulate cardiac electrical properties such as heart rate and QT interval via its receptor. In this work, the role of local direct actions of leptin on heart rate and ventricular repolarization was investigated. We identified the protein expression of leptin receptors at cell surface of sinus node, atrial, and ventricular myocytes isolated from rat heart. Leptin at low doses (0.1–30 μg/kg) decreased resting heart rate; at high doses (150–300 μg/kg), leptin induced a biphasic effect (decrease and then increase) on heart rate. In the presence of high-dose propranolol (30 mg/kg), high-dose leptin only reduced heart rate and sometimes caused sinus pauses and ventricular tachycardia. The leptin-induced inhibition of resting heart rate was fully reversed by leptin antagonist. Leptin also increased heart rate-corrected QT interval (QTc), and leptin antagonist did not. In isolated ventricular myocytes, leptin (0.03–0.3 μg/ml) reversibly increased the action potential duration. These results supported our hypothesis that in addition to indirect pathway via sympathetic tone, leptin can directly decrease heart rate and increase QT interval via its receptor independent of β-adrenergic receptor stimulation. During inhibition of β-adrenergic receptor activity, high concentration of leptin in myocardium can cause deep bradycardia, prolonged QT interval, and ventricular arrhythmias. PMID:26408544

Standardization of magnetocardiography in nonhuman primates

NASA Astrophysics Data System (ADS)

Seki, Yusuke; Muneyuki, Kenta; Kandori, Akihiko; Tsukada, Keiji; Terao, Keiji; Ageyama, Naohide

2008-03-01

To establish the electrophysiological mappings of nonhuman primates by using magnetocardiogram (MCG) data and obtain the normal values of MCG parameters, we used 64-channel superconducting quantum interference devices to measure 8 × 8 MCG data for 95 cynomolgus monkeys (Macaca fascicularis, 51 female and 44 male). The PQ interval, QRS duration, QT interval and QTc were respectively 79 ± 14 ms, 42 ± 7 ms, 222 ± 23 ms and 363 ± 25 (mean ± SD), and these parameters did not differ significantly between female and male monkeys. These results indicate the normal values of the MCG parameters of the cynomolgus monkey and should facilitate animal experiments in magnetocardiography.

Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study

PubMed Central

Boyce, Malcolm J; Baisley, Kathy J; Warrington, Steven J

2012-01-01

AIMS To assess the steady-state pharmacokinetic and QTc effects of domperidone and ketoconazole, given alone and together. METHODS A randomized, placebo-controlled, double-blind, crossover study was carried out. Healthy subjects (14 men, 10 women; age 18–39 years; mean weight 73.5 kg, range 53.8–98.8 kg; 23 Europid, 1 Afro-Caribbean) received orally, for 7 days each, placebo, domperidone 10 mg, four doses daily, at 4 h intervals, ketoconazole 200 mg 12-hourly and domperidone and ketoconazole together. The washout period was 15 days. Pharmacokinetics and serial 12-lead ECGs were assessed on day 7, and serial ECGs on day −1 and at follow-up. Two subjects withdrew before the third treatment period, so data were available for 22–24 subjects. RESULTS Ketoconazole tripled domperidone concentrations at steady-state. Domperidone, ketoconazole and their combination significantly increased QTcF in men. Overall adjusted mean differences from placebo were 4.20 (95% CI 0.77, 7.63), 9.24 (95% CI 5.85, 12.63) and 15.90 (95% CI 12.47, 19.33) ms, respectively. In women, QTcF was not significantly different from placebo on either domperidone or ketoconazole alone, or in combination. However, QTc was positively correlated with plasma drug concentrations, in both men and women. ΔQTcF increased by about 2 ms per 10 ng ml–1 rise in domperidone concentration, and per 1 µg ml–1 rise in ketoconazole concentration. CONCLUSIONS Ketoconazole tripled the plasma concentrations of domperidone. Domperidone and ketoconazole increased QTcF in men, whether given together or separately. The effect of domperidone alone was below the level of clinical importance. The negative result in women is unexplained. PMID:21883386

A pilot, open-label, 8-week study evaluating desvenlafaxine for treatment of major depression in methadone-maintained individuals with opioid use disorder.

PubMed

El Hage, Cynthia; Ghabrash, Maykel F; Dubreucq, Simon; Brissette, Suzanne; Lespérance, François; Lespérance, Paul; Ouellet-Plamondon, Clairélaine; Bruneau, Julie; Jutras-Aswad, Didier

2018-05-07

Depression is one of the most prevalent psychiatric disorders among opioid-dependent individuals. Clinical trials testing selective serotonin reuptake inhibitors among depressed patients on methadone maintenance therapy (MMT) failed to show efficacy, whereas those on tricyclic antidepressants produced mixed results with potential for cardiotoxicity. Desvenlafaxine (DESV) is a SNRI with minimal cardiotoxicity and drug interactions. This study sought to assess feasibility and tolerability of using DESV in depressed patients on MMT. A total of 18 depressed individuals on MMT received DESV (50-100 mg/day) for 8 weeks. Participants were assessed for the following: (a) Safety of DESV using Systematic Assessment for Treatment Emergent Events-GI, ECG [corrected Q-T (QTc) interval measurement] and methadone serum levels; (b) depressive symptoms using Montgomery-Äsberg Depression Rating Scale (MADRS); and (c) other outcomes including anxiety, suicidality, craving, substance use, quality of life, and other depression scales. Registration number on ClinicalTrials.gov is NCT02200406. Among participants who completed the study, MADRS scores significantly decreased at week 8 compared with baseline. Responders and remitters on MADRS at week 8 were 61 and 50%, respectively. There was no significant change in [corrected Q-T (QTc) interval measurement] between baseline and week 4. DESV was well tolerated and associated with improvement of depressive symptoms. DESV may be a promising contender to treat depression in individuals on MMT and deserves further exploration in a randomized double-blinded clinical trial.

Short-term effect of percutaneous recanalization of chronic total occlusions on QT dispersion and heart rate variability parameters

PubMed Central

Erdogan, Ercan; Akkaya, Mehmet; Bacaksız, Ahmet; Tasal, Abdurrahman; Sönmez, Osman; Asoglu, Emin; Kul, Seref; Sahın, Musa; Turfan, Murat; Vatankulu, Mehmet Akif; Göktekin, Omer

2013-01-01

Background QT dispersion (QTd), which is a measure of inhomogeneity of myocardial repolarization, increases following impaired myocardial perfusion. Its prolongation may provide a suitable substrate for life-threatening ventricular arrhythmias. We investigated the changes in QTd and heart rate variability (HRV) parameters after successful coronary artery revascularization in a patient with chronic total occlusions (CTO). Material/Methods This study included 139 successfully revascularized CTO patients (118 men, 21 women, mean age 58.3±9.6 years). QTd was measured from a 12-lead electrocardiogram and was defined as the difference between maximum and minimum QT interval. HRV analyses of all subjects were obtained. Frequency domain (LF: HF) and time domain (SDNN, pNN50, and rMSSD) parameters were analyzed. QT intervals were also corrected for heart rate using Bazett’s formula, and the corrected QT interval dispersion (QTcd) was then calculated. All measurements were made before and after percutaneous coronary intervention (PCI). Results Both QTd and QTcd showed significant improvement following successful revascularization of CTO (55.83±14.79 to 38.87±11.69; p<0.001 and 61.02±16.28 to 42.92±13.41; p<0.001). The revascularization of LAD (n=38), Cx (n=28) and RCA (n=73) resulted in decrease in HRV indices, including SDDN, rMSSD, and pNN50, but none of the variables reached statistical significance. Conclusions Successful revascularization of CTO may result in improvement in regional heterogeneity of myocardial repolarization, evidenced as decreased QTcd after the PCI. The revascularization in CTO lesions does not seem to have a significant impact on HRV. PMID:23969577

QT dispersion and ventricular arrhythmias in children with primary mitral valve prolapse

PubMed Central

İmamoğlu, Ebru Yalın; Eroğlu, Ayşe Güler

2016-01-01

Aim: To investigate ventricular arrhythmias in children with primary mitral valve prolapse and to evaluate its relation with QT length, QT dispersion, autonomic function tests and heart rate variability measurements. Material and Methods: Fourty two children with mitral valve prolapse and 32 healthy children were enrolled into the study. Twelve-lead electrocardiograms, autonomic function tests, echocardiography and 24-hour rhythm Holter tests were performed. Electrocardiograms were magnified digitally. The QT length was corrected according to heart rate. The patients were grouped according to the number of premature ventricular contractions and presence of complex ventricular arhythmia in the 24-hour rhythm Holter monitor test. Heart rate variability measurements were calculated automatically from the 24-hour rhythm Holter monitor test. Orthostatic hypotension and resting heart rate were used as autonomic function tests. Results: The mean age was 13.9±3.3 years in the patient group and 14.6±3.1 years in the control group (p>0.05). Thirty four of the patients (81%) were female and eight (19%) were male. Twenty five of the control subjects (78%) were female and seven (22%) were male. The QT dispersion and heart rate corrected QT interval were found to be significantly increased in the children with primary mitral valve prolapse when compared with the control group (56±16 ms vs. 43±11 ms, p=0.001; 426±25 ms vs. 407±26 ms, p=0.002, respectively). In 24-hour rhythm Holter monitor tests, ventricular arrhythmias were found in 21 out of 42 patients (50%) and 6 out of 32 control subjects (18.8%) (p=0.006). QT dispersion was found to be significantly increased in patients with premature ventricular contractions ≥ 10/day and/or complex ventricular arrhythmias compared to the control group without ventricular premature beats (p=0.002). There was no significant difference in autonomic function tests and heart rate variability measurements between the patient and control

The effects of diltiazem and metoprolol in QTc prolongation due to amitriptyline intoxication.

PubMed

Basol, Nursah; Erbas, Oytun

2016-01-01

Amitriptyline, a frequently used tricyclic antidepressant agent, has powerful cardiotoxic effects especially in high doses. Serum and urine levels of amitriptyline dosages are not correlated with severity of toxicity; therefore, it increases the importance of electrocardiography (ECG) abnormalities. The prolongation of QTc can be a predictive marker for cardiotoxicity. Hence, in this study, it is aimed to evaluate possible effects of metoprolol and diltiazem in amitriptyline toxicity. The rats were separated into four groups. First one was control group, the second was the amitriptyline + saline group, third one was the amitriptyline + metoprolol group, and forth one was the amitriptyline + diltiazem group. ECG were recorded on rats under anesthesia. In amitriptyline group, QTc duration was prolonged compared with all other groups. The prolongation of QTc was shorter in amitriptyline + metoprolol group and amitriptyline + diltiazem group than amitriptyline group (p < 0.01 and p < 0.01, respectively). According to the results, it is possible to report ameliorating effects of both metoprolol and diltiazem on QTc prolongation related with amitriptyline intoxication. With further studies, these agents may be used for amitriptyline toxicity and besides, they may be used for patients in cardiovascular risk groups who take amitriptyline treatment regularly. © The Author(s) 2015.

Prediction of Thorough QT study results using action potential simulations based on ion channel screens.

PubMed

Mirams, Gary R; Davies, Mark R; Brough, Stephen J; Bridgland-Taylor, Matthew H; Cui, Yi; Gavaghan, David J; Abi-Gerges, Najah

2014-01-01

Detection of drug-induced pro-arrhythmic risk is a primary concern for pharmaceutical companies and regulators. Increased risk is linked to prolongation of the QT interval on the body surface ECG. Recent studies have shown that multiple ion channel interactions can be required to predict changes in ventricular repolarisation and therefore QT intervals. In this study we attempt to predict the result of the human clinical Thorough QT (TQT) study, using multiple ion channel screening which is available early in drug development. Ion current reduction was measured, in the presence of marketed drugs which have had a TQT study, for channels encoded by hERG, CaV1.2, NaV1.5, KCNQ1/MinK, and Kv4.3/KChIP2.2. The screen was performed on two platforms - IonWorks Quattro (all 5 channels, 34 compounds), and IonWorks Barracuda (hERG & CaV1.2, 26 compounds). Concentration-effect curves were fitted to the resulting data, and used to calculate a percentage reduction in each current at a given concentration. Action potential simulations were then performed using the ten Tusscher and Panfilov (2006), Grandi et al. (2010) and O'Hara et al. (2011) human ventricular action potential models, pacing at 1Hz and running to steady state, for a range of concentrations. We compared simulated action potential duration predictions with the QT prolongation observed in the TQT studies. At the estimated concentrations, simulations tended to underestimate any observed QT prolongation. When considering a wider range of concentrations, and conventional patch clamp rather than screening data for hERG, prolongation of ≥5ms was predicted with up to 79% sensitivity and 100% specificity. This study provides a proof-of-principle for the prediction of human TQT study results using data available early in drug development. We highlight a number of areas that need refinement to improve the method's predictive power, but the results suggest that such approaches will provide a useful tool in cardiac safety

A high-risk patient with long-QT syndrome with no response to cardioselective beta-blockers.

PubMed

Toyota, Naoki; Miyazaki, Aya; Sakaguchi, Heima; Shimizu, Wataru; Ohuchi, Hideo

2015-09-01

We present a case of a high-risk 19-year-old female with long-QT syndrome (LQTS) with compound mutations. She had a history of aborted cardiac arrest and syncope and had received treatment with propranolol for 15 years. However, because she developed adult-onset asthma we tried to switch propranolol, a nonselective beta-blocker, to beta-1-cardioselective agents, bisoprolol and metoprolol. These resulted in both a markedly prolonged corrected QT interval and the development of LQTS-associated arrhythmias. Eventually, propranolol was reinitiated at a higher dose with the addition of verapamil, and she has had no further cardiac or asthmatic events for 5 years.

The Application of Root Mean Square Electrocardiography (RMS ECG) for the Detection of Acquired and Congenital Long QT Syndrome

PubMed Central

Lux, Robert L.; Sower, Christopher Todd; Allen, Nancy; Etheridge, Susan P.; Tristani-Firouzi, Martin; Saarel, Elizabeth V.

2014-01-01

Background Precise measurement of the QT interval is often hampered by difficulty determining the end of the low amplitude T wave. Root mean square electrocardiography (RMS ECG) provides a novel alternative measure of ventricular repolarization. Experimental data have shown that the interval between the RMS ECG QRS and T wave peaks (RTPK) closely reflects the mean ventricular action potential duration while the RMS T wave width (TW) tracks the dispersion of repolarization timing. Here, we tested the precision of RMS ECG to assess ventricular repolarization in humans in the setting of drug-induced and congenital Long QT Syndrome (LQTS). Methods RMS ECG signals were derived from high-resolution 24 hour Holter monitor recordings from 68 subjects after receiving placebo and moxifloxacin and from standard 12 lead ECGs obtained in 97 subjects with LQTS and 97 age- and sex-matched controls. RTPK, QTRMS and RMS TW intervals were automatically measured using custom software and compared to traditional QT measures using lead II. Results All measures of repolarization were prolonged during moxifloxacin administration and in LQTS subjects, but the variance of RMS intervals was significantly smaller than traditional lead II measurements. TW was prolonged during moxifloxacin and in subjects with LQT-2, but not LQT-1 or LQT-3. Conclusion These data validate the application of RMS ECG for the detection of drug-induced and congenital LQTS. RMS ECG measurements are more precise than the current standard of care lead II measurements. PMID:24454918

The application of root mean square electrocardiography (RMS ECG) for the detection of acquired and congenital long QT syndrome.

PubMed

Lux, Robert L; Sower, Christopher Todd; Allen, Nancy; Etheridge, Susan P; Tristani-Firouzi, Martin; Saarel, Elizabeth V

2014-01-01

Precise measurement of the QT interval is often hampered by difficulty determining the end of the low amplitude T wave. Root mean square electrocardiography (RMS ECG) provides a novel alternative measure of ventricular repolarization. Experimental data have shown that the interval between the RMS ECG QRS and T wave peaks (RTPK) closely reflects the mean ventricular action potential duration while the RMS T wave width (TW) tracks the dispersion of repolarization timing. Here, we tested the precision of RMS ECG to assess ventricular repolarization in humans in the setting of drug-induced and congenital Long QT Syndrome (LQTS). RMS ECG signals were derived from high-resolution 24 hour Holter monitor recordings from 68 subjects after receiving placebo and moxifloxacin and from standard 12 lead ECGs obtained in 97 subjects with LQTS and 97 age- and sex-matched controls. RTPK, QTRMS and RMS TW intervals were automatically measured using custom software and compared to traditional QT measures using lead II. All measures of repolarization were prolonged during moxifloxacin administration and in LQTS subjects, but the variance of RMS intervals was significantly smaller than traditional lead II measurements. TW was prolonged during moxifloxacin and in subjects with LQT-2, but not LQT-1 or LQT-3. These data validate the application of RMS ECG for the detection of drug-induced and congenital LQTS. RMS ECG measurements are more precise than the current standard of care lead II measurements.

Mutation of the Na+/K+-ATPase Atp1a1a.1 causes QT interval prolongation and bradycardia in zebrafish.

PubMed

Pott, Alexander; Bock, Sarah; Berger, Ina M; Frese, Karen; Dahme, Tillman; Keßler, Mirjam; Rinné, Susanne; Decher, Niels; Just, Steffen; Rottbauer, Wolfgang

2018-05-08

The genetic underpinnings that orchestrate the vertebrate heart rate are not fully understood yet, but of high clinical importance, since diseases of cardiac impulse formation and propagation are common and severe human arrhythmias. To identify novel regulators of the vertebrate heart rate, we deciphered the pathogenesis of the bradycardia in the homozygous zebrafish mutant hiphop (hip) and identified a missense-mutation (N851K) in Na + /K + -ATPase α1-subunit (atp1a1a.1). N851K affects zebrafish Na + /K + -ATPase ion transport capacity, as revealed by in vitro pump current measurements. Inhibition of the Na + /K + -ATPase in vivo indicates that hip rather acts as a hypomorph than being a null allele. Consequently, reduced Na + /K + -ATPase function leads to prolonged QT interval and refractoriness in the hip mutant heart, as shown by electrocardiogram and in vivo electrical stimulation experiments. We here demonstrate for the first time that Na + /K + -ATPase plays an essential role in heart rate regulation by prolonging myocardial repolarization. Copyright © 2018. Published by Elsevier Ltd.

Therapeutic effects of a taurine-magnesium coordination compound on experimental models of type 2 short QT syndrome.

PubMed

An, Meng-Yao; Sun, Kai; Li, Yan; Pan, Ying-Ying; Yin, Yong-Qiang; Kang, Yi; Sun, Tao; Wu, Hong; Gao, Wei-Zhen; Lou, Jian-Shi

2018-03-01

Short QT syndrome (SQTS) is a genetic arrhythmogenic disease that can cause malignant arrhythmia and sudden cardiac death. The current therapies for SQTS have application restrictions. We previously found that Mg· (NH 2 CH 2 CH 2 SO 3 )2· H 2 O, a taurine-magnesium coordination compound (TMCC) exerted anti-arrhythmic effects with low toxicity. In this study we established 3 different models to assess the potential anti-arrhythmic effects of TMCC on type 2 short QT syndrome (SQT2). In Langendorff guinea pig-perfused hearts, perfusion of pinacidil (20 μmol/L) significantly shortened the QT interval and QTpeak and increased rTp-Te (P<0.05 vs control). Subsequently, perfusion of TMCC (1-4 mmol/L) dose-dependently increased the QT interval and QTpeak (P<0.01 vs pinacidil). TMCC perfusion also reversed the rTp-Te value to the normal range. In guinea pig ventricular myocytes, perfusion of trapidil (1 mmol/L) significantly shortened the action potential duration at 50% (APD 50 ) and 90% repolarization (APD 90 ), which was significantly reversed by TMCC (0.01-1 mmol/L, P<0.05 vs trapidil). In HEK293 cells that stably expressed the outward delayed rectifier potassium channels (I Ks ), perfusion of TMCC (0.01-1 mmol/L) dose-dependently inhibited the IKs current with an IC 50 value of 201.1 μmol/L. The present study provides evidence that TMCC can extend the repolarization period and inhibit the repolarizing current, I Ks , thereby representing a therapeutic candidate for ventricular arrhythmia in SQT2.

Modelling PK/QT relationships from Phase I dose-escalation trials for drug combinations and developing quantitative risk assessments of clinically relevant QT prolongations.

PubMed

Sinclair, Karen; Kinable, Els; Grosch, Kai; Wang, Jixian

2016-05-01

In current industry practice, it is difficult to assess QT effects at potential therapeutic doses based on Phase I dose-escalation trials in oncology due to data scarcity, particularly in combinations trials. In this paper, we propose to use dose-concentration and concentration-QT models jointly to model the exposures and effects of multiple drugs in combination. The fitted models then can be used to make early predictions for QT prolongation to aid choosing recommended dose combinations for further investigation. The models consider potential correlation between concentrations of test drugs and potential drug-drug interactions at PK and QT levels. In addition, this approach allows for the assessment of the probability of QT prolongation exceeding given thresholds of clinical significance. The performance of this approach was examined via simulation under practical scenarios for dose-escalation trials for a combination of two drugs. The simulation results show that invaluable information of QT effects at therapeutic dose combinations can be gained by the proposed approaches. Early detection of dose combinations with substantial QT prolongation is evaluated effectively through the CIs of the predicted peak QT prolongation at each dose combination. Furthermore, the probability of QT prolongation exceeding a certain threshold is also computed to support early detection of safety signals while accounting for uncertainty associated with data from Phase I studies. While the prediction of QT effects is sensitive to the dose escalation process, the sensitivity and limited sample size should be considered when providing support to the decision-making process for further developing certain dose combinations. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Noninvasive cardiac activation imaging of ventricular arrhythmias during drug-induced QT prolongation in the rabbit heart.

PubMed

Han, Chengzong; Pogwizd, Steven M; Killingsworth, Cheryl R; Zhou, Zhaoye; He, Bin

2013-10-01

Imaging myocardial activation from noninvasive body surface potentials promises to aid in both cardiovascular research and clinical medicine. To investigate the ability of a noninvasive 3-dimensional cardiac electrical imaging technique for characterizing the activation patterns of dynamically changing ventricular arrhythmias during drug-induced QT prolongation in rabbits. Simultaneous body surface potential mapping and 3-dimensional intracardiac mapping were performed in a closed-chest condition in 8 rabbits. Data analysis was performed on premature ventricular complexes, couplets, and torsades de pointes (TdP) induced during intravenous administration of clofilium and phenylephrine with combinations of various infusion rates. The drug infusion led to a significant increase in the QT interval (from 175 ± 7 to 274 ± 31 ms) and rate-corrected QT interval (from 183 ± 5 to 262 ± 21 ms) during the first dose cycle. All the ectopic beats initiated by a focal activation pattern. The initial beat of TdPs arose at the focal site, whereas the subsequent beats were due to focal activity from different sites or 2 competing focal sites. The imaged results captured the dynamic shift of activation patterns and were in good correlation with the simultaneous measurements, with a correlation coefficient of 0.65 ± 0.02 averaged over 111 ectopic beats. Sites of initial activation were localized to be ~5 mm from the directly measured initiation sites. The 3-dimensional cardiac electrical imaging technique could localize the origin of activation and image activation sequence of TdP during QT prolongation induced by clofilium and phenylephrine in rabbits. It offers the potential to noninvasively investigate the proarrhythmic effects of drug infusion and assess the mechanisms of arrhythmias on a beat-to-beat basis. © 2013 Heart Rhythm Society. All rights reserved.

Risk of Cardiac Events Associated With Antidepressant Therapy in Patients With Long QT Syndrome.

PubMed

Wang, Meng; Szepietowska, Barbara; Polonsky, Bronislava; McNitt, Scott; Moss, Arthur J; Zareba, Wojciech; Auerbach, David S

2018-01-15

Patients with long QT syndrome (LQTS) are at a high risk of cardiac events. Many patients with LQTS are treated with antidepressant drugs (ADs). We investigated the LQTS genotype-specific risk of recurrent cardiac arrhythmic events (CAEs) associated with AD therapy. The study included 59 LQT1 and 72 LQT2 patients from the Rochester-based LQTS Registry with corrected QT (QT c ) prolongation and a history of AD therapy. Using multivariate Anderson-Gill models, we estimated the LQTS genotype-specific risk of recurrent CAEs (ventricular tachyarrhythmias, aborted cardiac arrest, or sudden cardiac death) associated with time-dependent ADs. Specifically, we examined the risk associated with all ADs, selective serotonin reuptake inhibitor (SSRI), and ADs classified on the CredibleMeds list (www.CredibleMeds.org) as "Conditional" or "Known risk of Torsades de pointes (TdP)." After adjusting for baseline QT c duration, sex, and time-dependent beta-blocker usage, there was an increased risk of recurrent CAEs associated with ADs in LQT1 patients (hazard ratio = 3.67, 95% confidence interval 1.98-6.82, p < 0.001) but not in LQT2 patients (hazard ratio = 0.89, 95% confidence interval 0.49-1.64, p = 0.716; LQT1 vs LQT2 interaction, p < 0.001). Similarly, LQT1 patients who were on SSRIs or ADs with "Known risk of TdP" had a higher risk of recurrent CAEs than those patients off all ADs, whereas there was no association in LQT2 patients. ADs with "Conditional risk of TdP" were not associated with the risk of recurrent CAEs in any of the groups. In conclusion, the risk of recurrent CAEs associated with time-dependent ADs is higher in LQT1 patients but not in LQT2 patients. Results suggest a LQTS genotype-specific effect of ADs on the risk of arrhythmic events. Copyright © 2017 Elsevier Inc. All rights reserved.

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vicente, Jose; Johannesen, Lars; Hosseini, Meisam

Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Furthermore, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.

Electrocardiographic Biomarkers for Detection of Drug-Induced Late Sodium Current Block

DOE PAGES

Vicente, Jose; Johannesen, Lars; Hosseini, Meisam; ...

2016-12-30

Drugs that prolong the heart rate corrected QT interval (QTc) on the electrocardiogram (ECG) by blocking the hERG potassium channel and also block inward currents (late sodium or L-type calcium) are not associated with torsade de pointes (e.g. ranolazine and verapamil). Furthermore, identifying ECG signs of late sodium current block could aid in the determination of proarrhythmic risk for new drugs. A new cardiac safety paradigm for drug development (the "CiPA" initiative) will involve the preclinical assessment of multiple human cardiac ion channels and ECG biomarkers are needed to determine if there are unexpected ion channel effects in humans.

Emerging therapeutic targets in the short QT syndrome.

PubMed

Hancox, Jules C; Whittaker, Dominic G; Du, Chunyun; Stuart, A Graham; Zhang, Henggui

2018-05-01

Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype-specific and non-specific treatments for the syndrome. Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K + channel inhibitors. A combination of K + current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K + channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8.

Drug-induced Inhibition and Trafficking Disruption of ion Channels: Pathogenesis of QT Abnormalities and Drug-induced Fatal Arrhythmias

PubMed Central

Cubeddu, Luigi X.

2016-01-01

Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interference with IKr is the most common cause of acquired LQTS/TdP. Multiple drugs bind to KNCH2-hERG-K+ channels affecting IKr, including antiarrythmics, antibiotics, antivirals, azole-antifungals, antimalarials, anticancer, antiemetics, prokinetics, antipsychotics, and antidepressants. Azithromycin has been recently added to this list. In addition to direct channel inhibition, some drugs interfere with the traffic of channels from the endoplasmic reticulum to the cell membrane, decreasing mature channel membrane density; e.g., pentamidine, geldalamicin, arsenic trioxide, digoxin, and probucol. Other drugs, such as ketoconazole, fluoxetine, norfluoxetine, citalopram, escitalopram, donepezil, tamoxifen, endoxifen, atazanavir, and roxitromycin, induce both direct channel inhibition and impaired channel trafficking. Although many drugs prolong the QT interval, TdP is a rare event. The following conditions increase the risk of drug-induced TdP: a) Disease states/electrolyte levels (heart failure, structural cardiac disease, bradycardia, hypokalemia); b) Pharmacogenomic variables (presence of congenital LQTS, subclinical ion-channel mutations, history of or having a relative with history of drug-induced long QT/TdP); c) Pharmacodynamic and kinetic factors (high doses, women, elderly, metabolism inhibitors, combining two or more QT prolonging drugs, drugs that prolong the QT and increase QT dispersion, and drugs with multiple actions on ion channels). Because most of these conditions are preventable, careful evaluation of risk factors and increased knowledge of drug use associated with repolarization abnormalities are strongly recommended. PMID:26926294

ECG-ViEW II, a freely accessible electrocardiogram database

PubMed Central

Park, Man Young; Lee, Sukhoon; Jeon, Min Seok; Yoon, Dukyong; Park, Rae Woong

2017-01-01

The Electrocardiogram Vigilance with Electronic data Warehouse II (ECG-ViEW II) is a large, single-center database comprising numeric parameter data of the surface electrocardiograms of all patients who underwent testing from 1 June 1994 to 31 July 2013. The electrocardiographic data include the test date, clinical department, RR interval, PR interval, QRS duration, QT interval, QTc interval, P axis, QRS axis, and T axis. These data are connected with patient age, sex, ethnicity, comorbidities, age-adjusted Charlson comorbidity index, prescribed drugs, and electrolyte levels. This longitudinal observational database contains 979,273 electrocardiograms from 461,178 patients over a 19-year study period. This database can provide an opportunity to study electrocardiographic changes caused by medications, disease, or other demographic variables. ECG-ViEW II is freely available at http://www.ecgview.org. PMID:28437484

Significance of screening electrocardiogram before the initiation of amitriptyline therapy in children with functional abdominal pain.

PubMed

Patra, Kamakshya P; Sankararaman, Senthilkumar; Jackson, Robert; Hussain, Sunny Z

2012-09-01

Amitriptyline (AMT) is commonly used in the management of children with irritable bowel syndrome. AMT is pro-arrhythmogenic and increases the risk of sudden cardiac death. However, there is not enough data regarding the cardiac toxicity in therapeutic doses of AMT in children and the need for screening electrocardiogram (EKG). Errors in computer EKG interpretation are not uncommon. In a risk-prevention study, the authors sought to identify the true incidence of prolonged corrected QT (QTc) interval and other arrhythmias in children with irritable bowel syndrome before the initiation of AMT. Out of the 760 EKGs screened, 3 EKGs demonstrated a true prolonged QTc after the careful manual reading by a pediatric cardiologist and they were not picked by computer-generated reading. The authors conclude that screening EKG should always be performed on children before initiating AMT therapy. Also, the computer-generated EKG needs to be verified by a pediatric cardiologist to avoid serious misinterpretations.

Electrocardiographic consequences of cardiac iron overload in thalassemia major

PubMed Central

Detterich, Jon; Noetzli, Leila; Dorey, Fred; Bar-Cohen, Yaniv; Harmatz, Paul; Coates, Thomas; Wood, John

2011-01-01

Background Iron cardiomyopathy is a leading cause of death in transfusion dependent thalassemia major (TM) patients and MRI (T2*) can recognize preclinical cardiac iron overload, but, is unavailable to many centers. Design and Methods We evaluated the ability of 12-lead electrocardiography to predict cardiac iron loading in TM. 12-lead electrocardiogram and cardiac T2* measurements were performed prospectively, with a detectable cardiac iron cutoff of T2*less than 20 ms. Patients with and without cardiac iron were compared using two-sample statistics and against population norms using age and gender-matched Z-scores. Results 45/78 patients had detectable cardiac iron. Patients having cardiac iron were older and more likely female but had comparable liver iron burdens and serum ferritin. Increased heart rate (HR) and prolonged corrected QT interval (QTc) were present, regardless of cardiac iron status. Repolarization abnormalities were the strongest predictors of cardiac iron, including QT/QTc prolongation, left shift of T-wave axis, and interpretation of ST/T-wave morphology. Recursive partitioning of the data for females using T-axis and HR and for males using QT, HR and T-axis produced algorithms with AUROC’s of 88.3 and 87.1 respectively. Conclusions Bradycardia and repolarization abnormalities on 12-lead electrocardiography were the most specific markers for cardiac iron in thalassemia major. Changes in these variables may be helpful to stratify cardiac risk when cardiac MRI is unavailable. However, diagnostic algorithms need to be vetted on larger and more diverse patient populations and longitudinal studies are necessary to determine reversibility of the observed abnormalities. PMID:22052662

Stressful life events and depressive symptoms among symptomatic long QT syndrome patients.

PubMed

Hintsa, Taina; Jokela, Markus; Elovainio, Marko; Määttänen, Ilmari; Swan, Heikki; Hintsanen, Mirka; Toivonen, Lauri; Kontula, Kimmo; Keltikangas-Järvinen, Liisa

2016-04-01

We examined whether long QT syndrome status moderates the association between stressful life events and depressive symptoms. Participants were 562 (n= 246 symptomatic) long QT syndrome mutation carriers. Depressive symptoms were measured with a modified version of the Beck's Depression Inventory. There was an interaction between long QT syndrome status and stressful life events on depressive symptoms. In the symptomatic long QT syndrome patients, stressful life events were associated with depressive symptoms (B= 0.24, p< 0.001). In the asymptomatic long QT syndrome mutation carriers, this association was 62.5 percent weaker (B= 0.09, p= 0.057). Compared to asymptomatic long QT syndrome mutation carriers, symptomatic long QT syndrome patients are more sensitive to the depressive effects of stressful life events. © The Author(s) 2014.

Degree Of Diminution In Vagal-Cardiac Activity Predicts Sudden Death In Familial Dysautonomia When Resting Tachycardia Is Absent

NASA Technical Reports Server (NTRS)

Schlegel, T. T.; Marthol, H.; Bucchner, S.; Tutaj, M.; Berlin, D.; Axelrod, F. B.; Hilz, M. J.

2004-01-01

Patients with familial dysautonomia (FD) have an increased risk of sudden death, but sensitive and specific predictors of sudden death in FD are lacking. Methods. We recorded 10-min resting high-fidelity 12-lead ECGs in 14 FD patients and in 14 age/gender-matched healthy subjects and studied 25+ different heart rate variability (HRV) indices for their ability to predict sudden death in the FD patients. Indices studied included those from 4 "nonlinear" HRV techniques (detrended fluctuation analysis, approximate entropy, correlation dimension, and PoincarC analyses). The predictive value of PR, QRS, QTc and JTc intervals, QT dispersion (QTd), beat-to-beat QT and PR interval variability indices (QTVI and PRVI) and 12- lead high frequency QRS ECG (150-250 Hz) were also studied. FD patients and controls (C) differed (Pless than 0.0l) with respect to 20+ of the HRV indices (FD less than C) and with respect to QTVI and PRVI (FDBC) and HF QRS- related root mean squared voltages (FDBC) and reduced amplitude zone counts (FD less than C). They differed less with respect to PR intervals (FD less than C) and JTc intervals (FD greater than C) (P less than 0.05 for both) and did not differ at all with respect to QRS and QTc intervals and to QTd. Within 12 months after study, 2 of the 14 patients succumbed to sudden cardiac arrest. The best predictor of sudden death was the degree of diminution in HRV vagal-cardiac (parasympathetic) parameters such as RMSSD, the SDl of Poincare plots, and HF spectral power. Excluding the two FD patients who had resting tachycardia (HR greater than 100, which confounds traditional HRV analyses), the following criteria were independently 100% sensitive and 100% specific for predicting sudden death in the remaining 12 FD patients during spontaneous breathing: RMSSD less than 13 ms and/or PoincarC SD1 less than 9 ms. In FD patients without supine tachycardia, the degree of diminution in parasympathetic HRV parameters (by high-fidelity ECG) predicts

[Effect of intermittent variable intensity exercise on QT variation and risk of sudden cardiac death among Cameroonian school adolescents].

PubMed

Bika Lele, E C; Pepouomi, M N; Temfemo, A; Mekoulou, J; Assomo Ndemba, P; Mandengue, S H

2018-02-01

Several cases of sudden deaths are observed among students practicing sport and physical activity (SPA). Just few studies have been carried out on the variation of the QT (interval) and risk of sudden death during sporting exercises. To determine the effect of variable intermittent stress intensity on the variation of QT and the risk of sudden cardiac death. Form 4, lower sixth and upper sixth students were recruited from a high school in Douala (Cameroon). Each subject was tested; starting with a 2-km walk followed by a sprint race or an endurance race, protocol I (P1) or the reverse; protocol II (P2). Two electrocardiograms were recorded; prior to the beginning of the SPA and 5minutes after the last race. QT was corrected using four formulas. Forty-one subjects (21 women and 20 men), mean age 18±2 years were recruited. At the end of the exercise, corrected QT increased with Bazzet's formula and decreased with Frahmingam's formula. The difference was not significant with Fridericia and Hodges formulas. The frequency of long QT was higher at the end of the exercise with Bazzet's formula (12.2% vs. 24.4%, P=0.009) while the difference was not significant for the other formulas. The risk of sudden cardiac death increases significantly after SPA. More studies on large samples are needed. Copyright © 2017. Published by Elsevier SAS.

[Long QT syndrome and polymorphic ventricular tachycardia due to hypopituitarism. Report of one case].

PubMed

García-Castro, José Miguel; García-Martín, Antonia; Guirao-Arrabal, Emilio; Carrillo-Alascio, Pedro Luis

2017-07-01

Symptoms of hypopituitarism are usually chronic and nonspecific, but rarely the disease can have acute and life threatening manifestations. We report a 53 years old female with a pituitary adenoma that was admitted to our hospital because of syncope. The electrocardiogram showed sinus bradycardia with a prolonged QT interval. Frequent runs of non-sustained polymorphic ventricular tachycardia were noted on telemetry. The patient had a history of severe acute headaches in the previous days and laboratory tests revealed severe secondary hypothyroidism, adrenal insufficiency and a decrease in pituitary hormones. A magnetic resonance imaging of the head showed changes in the size and contrast enhancement of the adenoma. A diagnosis of hypopituitarism secondary to pituitary apoplexy was made and treatment with hydrocortisone and, subsequently, levothyroxine was started. Hormonal disorders such as hypothyroidism, adrenal insufficiency or hypopituitarism should be considered as unusual causes for reversible cardiomyopathy, long QT syndrome and ventricular arrhythmias.

Mianserin, maprotiline and intracardiac conduction

PubMed Central

Edwards, J. Guy; Goldie, Ann

1983-01-01

1 High speed surface electrocardiograms were recorded in 35 patients during the baseline and after four weeks' treatment in a placebo-controlled trial of mianserin and maprotiline in primary depressive illness. 2 Measurements of the RR, PR and QT intervals, QRS width and T wave height were made blind to patient, drug and treatment interval and compared with plasma drug concentrations. The presence or absence of cardiac arrhythmias was recorded. 3 The only significant findings were an increased heart rate and PR interval and decreased QTc interval in the maprotiline group. Only one patient receiving maprotiline had a cardiac arrhythmia. There was no significant correlation between measurements of ECG parameters and plasma drug levels. 4 The results confirm the lack of cardiac effects of mianserin and show both anticholinergic activity and effects of an intracardiac conduction in the case of maprotiline. The mechanisms of these effects are discussed. PMID:6824556

[Comparative analysis of parameters of corrected and uncorrected QT-interval dispersion of magneto-, electrocardiography and isomagnetic maps in patients with ischemic heart disease].

PubMed

Shabalin, A V; Tret'iakova, T V; Kuznetsov, A A; Motorin, S V; Golyshev, N V

2002-01-01

To compare possibilities of magnetocardiography (MCG) and electrocardiography for assessment of regional dispersion of ventricular recovery time using parameters of corrected and uncorrected QT-interval dispersion (DQTs and DQT). Twenty three patients with class II angina pectoris including 11 patients with history of myocardial infarction (MI) and 13 practically healthy subjects. Mean DQT and DQTc were significantly higher (p<0.005) in patients than in healthy subjects according to both techniques. Values of DQT and DQTc obtained by MCG were higher in patients with history of MI compared with those without MI (p=0.006 and 0.02, respectively). There was a significant positive correlation between age and DQT and DQTc determined by electrocardiography. Mean number of T-wave dipoles was significantly higher in patients than in healthy subjects. Substantial positive correlation was found between number of T-wave dipoles on isomagnetic maps and age in both patients and healthy people. The method of MCG gave supplementary information on the state of ventricular depolarization in patients with ischemic heart disease.

Two markers in predicting the cardiovascular events in patients with polycystic ovary syndrome: increased P-wave and QT dispersion.

PubMed

Akdag, S; Cim, N; Yildizhan, R; Akyol, A; Ozturk, F; Babat, N

2015-09-01

Polycystic ovary syndrome (PCOS) is a prevalent disease with many potential long-term cardiovascular risks. P-wave dispersion (Pdis) and QT dispersion (QTdis) have been shown to be noninvasive electrocardiographic predictors for development of cardiac arrhythmias. In this study we aimed to search Pdis and QTdis parameters in patients with PCOS. The study included 82 patients with PCOS and 74 age- and sex-matched healthy controls. Baseline 12-lead electrocardiographic and transthoracic echocardiographic measurements were evaluated. P-wave maximum duration (Pmax), P-wave minimum duration (Pmin), Pdis, QT interval, heart rate-corrected QT dispersion and QTdis were calculated by two cardiologists. Patients wirh PCOS had significantly higher QT dispersion (49.5 ± 14.1 vs. 37.9 ± 12.6 ms, p < 0.001), and P wave dispersion (54.2 ± 11.4 vs. 45.9 ± 10.1 ms, p < 0.001) than the controls. Serum testosterone and estradiol levels was correlated with the Pdis (r = 0.677, p < 0.001 and r = 0.415, p < 0.001 respectively) and QTdis (r = 0.326, p < 0.001 and r = 0.321, p < 0.001 respectively). Pdis and QTdis are simple and useful electrocardiographic markers which may be used in the prediction of the risk of adverse cardiovascular events in PCOS patients.

Psychotropic Pharmacotherapy Associated With QT Prolongation Among Veterans With Posttraumatic Stress Disorder.

PubMed

Stock, Eileen M; Zeber, John E; McNeal, Catherine J; Banchs, Javier E; Copeland, Laurel A

2018-04-01